DE2549417A1 - NEW BENZENE DERIVATIVES - Google Patents

Description

New benzene derivatives

The invention relates to new benzene derivatives, compositions containing them and their use as anthelmintics or Anthelmintics and agents effective against fungi.

On the basis of investigations and experiments it could be determined that new benzene derivatives of the general formula

NHCSNHCOOR ²

NHC0A2

valuable chemotherapeutic properties, especially high anthelmintic activity and a have high activity against fungi. In this formula I, R denotes a straight-chain or branched alkyl group

more than 4 carbon atoms (preferably methyl), R denotes a group of the formulas -SR ^, -SOR ^, -SO ₂ R- ^, -OR ?, -SCONH ₂ , -SCN or -T (CHg) _1n T ¹ R * [where B? a straight chain or

609831/1003

ORIGINAL INSPECTED

26494Π

branched chain alkyl group of not more than 6 carbon atoms represents, e.g., methyl or ethyl, a cycloalkyl group with 3 to 7 carbon atoms, e.g. cyclopentyl, a straight chain or branched chain alkenyl or alkynyl group with

3 to 6 carbon atoms, for example allyl or prop-2-ynyl, an aralkyl, for example phenylalkyl, group with 1 or 2 carbon atoms in the alkyl part, for example benzyl, or B? denotes an aryl group, for example phenyl group, which can optionally be substituted by a halogen (for example chlorine) atom or a straight or branched chain alkyl or alkoxy group having 1 to 3 carbon atoms, or denotes a cycloalkylalkyl group in which the cycloalkyl moiety j5 to Contains 7 carbon atoms and the alkyl part contains 1 or 2 carbon atoms, for example cyclohexylmethyl, R denotes a hydrogen atom or preferably a straight or branched chain alkyl group with no more than

4 carbon atoms, e.g. ethyl, T and T, which are the same or different can be, each represent an oxygen or sulfur atom or a sulfinyl (- SO -) group and m is one integer from 1 to 7 inclusive and preferably 2], the position of which on the benzene ring is either para to the -NHCSNHCOOR group or para to the -NHCOAZ group, A denotes a divalent straight-chain aliphatic hydrocarbon radical with no more than 4 carbon atoms, which is saturated or may be unsaturated (e.g. a methylene, polymethylene, e.g. ethylene, or vinylene radical) and the optionally may be substituted by at least one methyl group, and Z denotes a group of the general formulas

II IXI

wherein Br represents a hydrogen atom or a straight or branched chain alkyl group with not more than 4 carbon atoms, for example methyl or ethyl, R represents a hydrogen atom or a straight chain or branched chain alkyl group with

609831/1003

- ^ - 2bAü417

no more than 4 carbon atoms, e.g. methyl or ethyl, or a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part, preferably benzyl, and R ¹ denotes a hydrogen atom or a straight-chain or branched-chain alkyl group with no more than 4 carbon atoms, e.g. methyl or ethyl , or R and R together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocyclic ring, which can contain one or two further heteroatoms in the ring, selected from oxygen, nitrogen and sulfur, and which can optionally be substituted by one or more straight-chain or branched-chain alkyl groups having not more than 6 carbon atoms, for example a pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl or 4-alkylpiperazin-1-yl -, for example 4-methylpiperazin-1-yl group and x - denotes a pharmaceutically acceptable or agriculturally acceptable anion.

If the compounds of general formula I can exist in stereoisomeric forms, then all such isomers are and their mixtures and racemates included within the scope of the invention.

The term "pharmaceutically acceptable anion" means an anion which is active against the animal or human organism is relatively harmless when used in therapeutic doses such that the desired properties of the Cations are not affected by side effects related to the anion.

The term "agriculturally acceptable anion" means an anion that is generally intended for use in the agricultural sector Practice can be considered acceptable, although it is relatively harmless to plant organisms, if it is used in doses of fungicidal use in such a way that the valuable properties of the cation are not carried through side effects attributable to the anion are impaired.

Good examples of anions within the definition of X ~

609831/1003 ORIGINAL INSPECTED

-4- 2543417

are halogen ions (e.g. chloride, bromide and iodide ions) and the methanesulfonate, sulfate, nitrate, phosphate, acetate, Citrate, propionate, succinate, benzoate, fumarate, maleate, · Tartrate, theophylline acetate, salicylate, phenolphthalinate, Methylene bis-ß-hydroxynaphthoate, amsonate and isothionate ion.

In accordance with one feature of the present invention, there is provided a method of treating human and domestic animal infections e.g. in cattle, sheep, pigs, goats, poultry and horses, e.g. infections of the gastrointestinal tract caused by parasitic nematode worms, e.g. by members of the Trichostrongylidae family, and infections by parasitic trematodes of the species Fasciola (e.g. Fasciola hepatica, also known as liver fluke) in domestic animals that have the Administration of an anthelmintically effective amount of one or more compounds of the general formula I comprises, ready be asked.

The amounts of the compounds of formula I administered for the treatment of helminthiasis will vary with the Species of animal to be treated, the nature and severity of the infection, the length of treatment and the method of administration. In general, the compounds are effective in treating helminthiasis when given in dosages to pets administered, which can be as low as 1 mg / kg animal body weight, but which are preferably about 4 mg / kg to approx. 50 mg / kg animal body weight. Higher doses up to However, 250 mg / kg animal body weight can also be used.

The amounts given above of the compounds of the general Formula I can be administered on one or more occasions, or in a number of smaller doses and administered over a period of time.

The value of the compounds of formula I as anthelmintics could for example be shown in the following tests.

3983 1/1003 ORIGINAL INSPECTED

In Tables I and V below, the forms in which the test compounds were administered are in those with "Form" indicated columns in which the symbols have the following meanings:

"B" means that the free base was used (i.e. a compound in which Z is a group of formula III),

"C" means the hydrochloride was used (i.e. a Compound in which Z is a group of the general formula II in which R ^ is a hydrogen ion and X® is a chloride ion means) and

"M" means that the methanesulfonate salt was used (ie, a compound in which Z is a group of Formula II where R ^ is a hydrogen ion and XP ^{1 is} a methanesulfonate ion).

Where indicated that a methanesulfonate salt is administered where, however, the specific methanesulfonate salt in detail not described in the following preparative examples, the methanesulfonate salt was obtained by treating the free base with 0.2N aqueous methanesulfonic acid solution in equimolecular proportions and subsequent dilution with water to a volume suitable for administration.

A. Activity against roundworms in rats Test 1

Rats were each with 100 Nippostrongylus brasiliensis larvae infected by the subcutaneous route. After 6 days, after which the When infection was evident, the rats were randomized and divided into groups of 5 ready-to-treat animals divided up. One group was given for each dose level of the test compound administered by the oral or subcutaneous route was used and in each experiment a group of 10 animals was left untreated as controls. All rats were

60 9 831/1003

sacrificed 48 hours after treatment for a post-mortem counting of worms.

The activities, expressed as a percentage reduction in the mean worm load of the treated groups compared to the untreated groups, are given in Table I.

Test 2

Rats were infected with 100 Nippostrongylus brasiliensis larvae by subcutaneous route. After 24 hours, the rats were randomly divided and divided into groups of 5 animals ready for treatment. The doses of test compound were then administered to each group by the oral or subcutaneous route, with a group of 10 animals being untreated as controls. All rats were sacrificed for post mortem worm counting 6 days after administration. The activities, expressed as a percentage reduction in the mean worm load of the treated groups compared to the untreated control group, are given in Table I below.

Test 3

Rats were infected with 100 Nippostrcngylus brasiliensis larvae by subcutaneous route. After 24 hours, the rats' back hair was clipped, taking care to avoid damaging the skin, and the rats were randomized and divided into groups of 5 animals ready for treatment. The animals were then anesthetized, a 10 % w / v solution of the test compound in dimethyl sulfoxide was applied topically to the shaved area of each animal in the group, with a group of 10 animals being untreated as controls. Dimethyl sulfoxide solvent was also applied topically to the shorn area of each animal in a separate group of 5 animals. All rats were sacrificed for post-mortem worm enumeration 6 days after treatment.

6 0 9 8 3 1/10 0 3

The percentage reduction in the mean worm load of the treated groups compared to the untreated control group Activities expressed are given in Table II below.

In the tables, "se" means "subeutane".

609831/1003

Table I.

ta co approx

approx

Test connection T
E.
S.
T F.
0
R.
M. Dose mgAg
Carcasses
weight ■ Meet
route Percentage Reduk
tion of the N. bra
siliensis loading H ^ (3-methoxycarbony1-2-
thioureido) -3- (2-dimethyl-
aminoacetamido) diphenyl
thioether 1
1
2
2
2
2 B.
M.
B.
B.
B.
M. 100
100
250
100
25th
25th orally
SC
orally
orally
orally
SC 100
31
100
100
99 '
99 3- (3-methoxycarfconyl-2-
thio ureido) - '<■ - (2 -dimethyl -
aminoacetarrldo) diphenyl
thioether 1
1
2
2 C.
M.
C.
M. 100
100
25th
25th orally
SC
orally
SC 99
36
99
88 h- (2-aminoacetaraido) -3-
(3-metlioxy carbonyl-2-
thioureido) diphenyl
thioether 1
1
2
2 B.
M.
B.
M. 50
50
12.5
12.5 orally
SC
orally
SC 97
96
99
99 h- (2-aminoacetamido) -3-
(3-ethoxycarbonyl-2-
thioureido diphenyl
thioether 2 B. 50 orally 95

oo

NJ cc

Table I (port setting)

fet »

co

Test connection T P. Dose mg / kg Meet Percentage Reduk > E. 0 Carcasses route tion of the N .- * brasi- S. R. weight liensis loading T M. 3- (3-Wetho3cycarbonyl ~ 2- 2 B. 12.5 oral. 99 thioureido) -if- [2- (N-methyl- 2 M. 25th SC 99 Π araino,) acetamido] diphenyl- 2 M. 12.5 SC 96 D. thioether 1 B. 100 orally 97 3- (2-AminoacGtamido) - ^ -. 1 B. 100 orally 99 {3 ~ mGthoi: carbonyl-2- 1 M. loo SC Sk thioureido) diphenyl 2 B. 50 orally 99 thioether 2 M. 50 SC 99 k- { 2-aminoacetamido) -3- 1 B. 100 orally Qk (3-metho; cy carbonyl- 2- 1 M. 100 SC 62 thioureido) -h '-methyl 2 B. 25th orally 95 dipheny1 thioether 2 . 14th 50 · 3C 9k h '- chlorine - 3 - (3 -methoscy- 1 B. 100 orally 92 carbonyl-2-thioureido) - 2 3 50 orally 99 h- { 2-dimethylamino- 2 M. 50 • se 9k acetainido) diphenyl thioether 3- (2-A minoacetarrddo ) -h * 1 B. 100 orally 90 (3-methojcycarbonyl ** 2- 1 M. 100 SC 3 ^ Ϊ * thioureido) diphenyl 2 "B. 50 orally 97 <; ether 2 M. 50 SC 98 ·
P.

Table I (port setting)

• o as

CaJ

Test connection T
Ξ
S.
T P.
0
R.
M. Dose mg / fcg
Feral
weight Meet
route Percentage Reduk
tion of the N. brasi-
llensls loading k- (3-methoxycarbonyl-2-
thioureido) -3- (2-dimethyl-
arainoacetamido) diphenyl—
ether to to C.
C. 100
100 orally
SC 97
61 3- (3-methoxycarbonyl-2-
thioureido) - ^ '- methyl
k- (2-dirnethylamino-
acetarnido) diphenyl -
thioether 1
2
2 B.
B.
M. 100
100
100 orally
orally
SC 56
97
51 Zf- (2-Aminoacetamido ) * - h '-
chlorine — 3 - (3-metliojcy-
carfconyl-2-p.iouroido) -
diphenyl-thicoether 1
1
2
2 3
M.
B.
M. 100
100
50
100 orally
SC
orally
SC 93
75
100
99 h- ( 3-M3tho;: ycarbonyl-2-
thioureido) -3- (2-
pyrrolidin-1-ylacetamido) -
dipheny1-thio ether 1
2
2 B.
B-
M. 100
25th
25th orally
orally
se 93
99
7a 2- (3-fithoxycarbonyl-2-
thioureido) ~ l- (2 ~ dimethyl-
aminp acetamido) -i} -methyl-
sulfony! benzene 1
2
2 C.
C.
C. 100
100
250 orally
orally
SC 61
96
. 92

he. • Ρα?

Table I (port setting)

Test connection T
E.
S.
T P.
0
R.
M. Dose mg / kg
Carcasses
weight Meet
route Percentage Reduk
tion of the N. brasi-
liensis loading ty- (3-Ntethoxycarbonyl-
2-thioureidö) -3 ~ (3-
ddmothy 1 am inop ropionamido) -
diphenyl thioether 1
2
2 B.
B.
M. 100
50
50 orally
orally
SC 50
99
95 3- (2-DLethylamino-
acetamido) -k ~ (3 * -methoxy-
carbonyi-2-thioureido) -
diphenyl thioether 1
2
2 B.
B.
M. 100
25th
25th orally
orally
SC 99
98
98 1- (3- jyfcthoxy carbonyl-2-
thioureido) -3- (2-dimethyl-
arnino acetamido) -
ty-methylthiohenz oil. CM CM B.
M. 100
100 orally
SC 87
97 thiouroido) ~ 3- (2-diraethyl-
aminoacetamido jdiphenyl-
sulfoxide I NJH C.
C. 100
50 orally
orally 99
100 ty-allylthio ~ l- (3 ~ methoxy ~
carbonyl-2-tliiourGido) -2-
(2-dimethylaminaacGtamido) -
benzene H HCM CM B.
M.
B.
M. 100
"100
50
50 ο rai
se
orally
SC 81
97
97 3r (2 - diethy laraino-
acetamido) -ty- (3-nethoxy-
, carbonyl-2-thiouroido) -
diphenyl ether 1
2
2 C.
c.
C. 100
50
100 orally
orally
SC 65
9 ty
97

Table I (continued)

&
Φ

Test connection T
E.
S.
T P.
0
R.
M. Dose: mg / kg
Carcasses
weight Administration
route Percentage Reduk
tion of the N. brasi-
liensis loading 4-benzylthio-1- (3-metho: cy-
car33onyl-2-thioureido) -2-
(2-dimethylaininoacetaniido) -
benzene 1
1
2
2 B.
M.
B.
M. 100
100
50
50 orally
SC
orally
SC 93
70
98
95 ^ -Ethylthio-l- (3-methoxy-
carbonyl-2-thioureido) -2-
(2 ~ diraethylaminoacetanido J-
benzene 1
2
2 B.
B.
M. 100
50
50 orally
orally
SC 86
92
92 4-n-butylthio-l- (3-
netho5: y ca rbonyl -2 - thio-
ureido) ~ 2- (2-dimethyl-
arainoacetamido) -
bensol 1
1
2
2 B.
M.
B.
M. 100
100
50
50 orally
SC
orally
SC 88
1 »8
97
93 ^Λ h - (3 ~ metho :: carbonyl-2-
thioureido) -3- (2-dimethyl-
aiuinoprop ionainido) djphGnyl
thioether 1
2
2 B.
B.
M. 100
12.5
25 ' orally
orally
SC 100
95
95 i4-Cyclopentyltnio ~ l- (3-
metho: r / carbonyl-2-thio-
ure ido) - 2 - (2 -dime thy 1-
ar.iinoacGtamido) benzene 2
2 B.
M. 50
'100 orally
SC 93
90 Zi- (2-ethylthioethyltl.io) -
1- (3-jrnetho: cy carhonyl-2-
thioureido) -2- (2-dimethyl-
aiainoacetaraido jbenzene 2
2 B.
M. 100
100 orally
SC 92
69

Table II

Test connection Dose rag / kg.
Carcass. . Percentage reduction in "
N. brasillensis worm load k- (3-Metho3cycarbonyl-2-thiour eido) -
3- (2-dimethylaiainoacetamido) -
diphenylthioether 200 99 h- (3-Metlioxycarbonyl-2-thioureido) -
3- (2-dimethylaminoacetarnj do) -
diplienyl thioä the r- metlian-
sulfonate 200 99
\ Dimethyl sulfoxide -
solvent 2000 0

B. In vitro activity against roundworms

Compounds of the formula I were examined in concentrations of 100 10 jig / ml, 1 / ag / ml and 0.1 ig / ml in small glass containers. If the compound was not soluble in water, it became a volatile organic medium, e.g. acetone, chloroform, ethanol or methanol is used. An appropriate amount of material for each final concentration was determined and placed in duplicate test containers and, if an organic solvent was used, it was allowed to completely evaporate.

Nippostrongylus brasiliensis eggs were obtained by centrifugal flotation in a saturated saline solution obtained from the feces of rats that had been infected 6 days earlier with larvae in the third instar were severely infected. They were washed several times in water and suspended in water at an appropriate concentration. 25 to 50 eggs were placed in each container, and the final volume was obtained by adding a very dilute aqueous suspension of mouse feces, which served as a growth medium.

The minimum inhibitory activity given in Table III below Concentration of any compound (M.I.C.) is the minimum Concentration in µg / ml total volume of liquid at which the hatching of eggs has been inhibited or delayed, or which has been killed, the growth has been delayed or which Activity of the larvae was reduced 4 days after the start of the test.

60 9 8 31/1003

Table III

CO CO Ca>

O Q CO

Link . M.I.C. (p.g / ml) it -. (3-Methoxycarbonyl-2-thioureido) ~ 3- (2-dimethyl-
aminoacetamido) diphenyl thioether ■ O _f l 3- (3-methoxycarbonyl-2-thioureido ) -kX 2-diraethyl-
arninoacetaitiidojdiphenyl thioether hydrochloride 0.1 4- (2-aminoacetamido) -3- (3-methoxycarbonyl-2-
thioureido) diphenyl thioether °, i. h- (3-methoxycarbonyl-2 ~ thioureido) -3- (2-triraethyl-
ammonioacetylamirio) diphenyl thioether ^ odide ° ₅ i k ~ { 2-Arainoacetamido) -3- (3-ethoxycarbonyl-2-
thioureido) diphenyl thioether ⁰ ^ 3- (2-Aminoacetamido) ~ k- (3-methoxycarbonyl ~ 2-
thioureido diphenyl thioether 100 h- (2-Aminoacetamido) -3- (3-methoxycarbonyl-2-
thioureido ) ~ k'-methyldiphenyl thioether ° / l 4'-chloro-3- (3-metho> r / carbonyl-2 ~ thioureido) -
-! j - C2-dimethylaminoacetarnido) diphGnyl-thioether 3- (2-Aminoacetamido ) -k- (3r-metho5cycarbonyl-2-
thioureido) diphenyl ether °> i ^ ~ (.3-Methoxycarhonyl-2-thioureido) -3- (2-dimethyl ~
aminoacetamidojdiphenyl ether hydrochloride ομ

Table III (port setting)

cn ο co OO Ca>

O CD ILO

, Link M.I.C. (Hg / ml) 3- (3-Metho3cycar: bonyl-2-thioureido) -k * -methyl-
Z ₁ .- (2-dimethylaminoacet amido) diphenyl thioether k- (2-aminoacetamido) -k * -chlor -3- (3-methoxy-
carbonyl-2 - tliiour eido) diphenyl - thio ether ο, ι Z (~ (3-Metho ^ ycarbonyl-2-thioureido) -3- (2-pyrrolidine-
l-ylacetamido) diphenyl thioether ομ h- { 3hyieitho; iycarbonyl-2-thioureido) -3- (2-xnorpholine-
/ i-ylacetamido) diphenyl thio ether ομ k- (3-Metho3r / carbonyl-2-thiour eido) -3- (3-diraethyl-
aminopropionamido) diphenyl thioether ο, ι 3- (2-D.iäthylaminoacetamido) - ^ ι- (3-methoxycarbonyl-
2-thioureido) diphenyl-thio ether 0.1 l- (3-Methocycarbonyl-2-thioureido) -2- (2 -dimethyl -
arainoac et amido) -A-methylthiobenzene 1.0 h- (3-n-buto; cycarbonyl-2-thioureido) -2- (2-dimethyl
aininoacetar.iido) diphenyl thioether ομ 4-Allylthio-l- {3-method arbony 1-2-thiour eido) -2-
(2-diraGthyla; ninoacetamido Jbenzol °, ι

H*

Cn -Ο- CO

Table III (port setting)

O O UJ

link MIC [μς / ταΐ) 3- (2-Dimethylaminoacetamido) - ^ - [3- (2-methyl-
propoxycarbonyl) -2-thioureido] diphenyl- * thioether 10.0 3- (2 "-Diethylaminoacetamido) - '■! - (3-metho3cy-
carbonyl-2-tliioureido) diphenyl-ether-hydrochloride (2 0.1 Jt-Banzylthio-l- (3-methoxy car bony l ~ 2-thiour eido) -
2- (2-dimethylaminoacetatenido) ben2ol 0.1 / 4- Ethylthio-1- (3-inethoxycarbony 1-2-thiour eido) -
2- (2-dimethylaminoacetamido) benzene 0.1 J ^ -n-Butylthio-1- (3-methoxy carbonyl-2 ~ thioureido) -
2- (2-diraGthylaminoacGtamido) benzene 0.1 i) .- (3-metho;: ycarbonyl ~ 2-thioureido) -3- (2-diniethyl-
aminopropionamido) diphenyl ~ thio ether 0.1 ii-Qi ^ clopentylthio-lt 3-methoxycarbonyl-2-thiour eido) -
2- (2 ~ diraethylaminoacetamido) benzene 0.1

" ¹⁸ '2 5 A 9 41 7

C. Activity against roundworms in sheep

(a) Activity against Haemonchus contortus and Nematodirus later in their developed stages in lambs.

Worm-free 8-10 week old lambs were infected with 5000 H. contortus and 15000 N. spathiger larvae. Approximately 3 weeks later, doses of the test compound were administered to each group of 2 animals by either the oral or subcutaneous route, a group of 2 animals remained untreated for comparison.

Individual fecal H. contortus egg counts were taken one day before and 5-7 days after treatment as all Lambs killed for the post mortem worm count were performed. The percentage reduction in the mean worm load of each worm species compared to the untreated one Activities reported for control groups are listed in Table IV below.

(b) Activity against Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis and nematodirus later in their fourth larval instar and fully developed stages in lambs.

Worm-free 8-10 week old lambs were each given 5000 H. contortus- ^, 15000 0.circumcincta-, 20000 T. axei-, 15000 T. colubriformis and 150,000 N. spathiger larvae infected.

Each group of 2 animals was given either oral or subcutaneous or by the intramuscular route 7 days or 21 days thereafter, doses of the test compound are administered to counteract the effect the fourth larval stage or the fully matured worms, with a group of 2 animals for comparison remained untreated. All lambs were sacrificed for post mortem worm counts 24 days after infection. In the Form of the percentage reduction in the mean worm load of each worm species compared to the untreated one

609831/1003

Activities expressed in control group are given in Table V below. Table V is as follows Test connections:

4- (5-Methoxycarbonyl-2-thioureido) -3- (2-dimethylamino-acetamido) -diphenyl-thioether (P),

4- (35-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether (Q),

4-r (2-Arainoacetamido) -3- (3-methoxycarbonyl-2-thioureido) -diphenylthioether (R),

4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl ether (S),

5r (2-diethylaminoacetamido) -4- (3-methoxycarbonyl-2-thioureido) diphenyl thioether (T) and 4- (3-methoxycarbonyl-2-thioureido) -3- (3-dimethylaminopropionamido) diphenyl thioether (U).

609831/1003

Table XV

Test connection Dose mg / kg
Carcass
weight" Disposition
route Percentage reduction in
medium worm load N. spathicjer 4- (3-ethoxycarbonyl
2-thioureido) -3- (2-dimethyl-
amirioacet amido) diphenyl-
thioether 10
5 orally
orally H. contortU3 100
87 4- (3-methoxycarbonyl-
2-thioureido) -3- (2-dimethyl-
aminoacetamido) diphenyl ~
thioether methanesulfonate 25th
10 SC
SC 100
5k 3- (3-methoxycarbonyl-
2-thioureido ) -h- (2-dimethyl-
aminoacetamido) diphenyl
thioether hydrochloride, 10 orally 100
100 86 3- (3-methoxycarbonyl-
2-thioureido) - ^ - (2-dimethyl-
aminoacetai "iiido) diphenyl ~
thioether methanesulfonate ■ - ' 10 SC 100
100 63 h- ('2-Airiinoacetamido) -3- (3-
raetho2: ycarbonyl-2 -thioureido) -
diphenyl thioether 10 orally 100 30th 100 100

Table IV (continued)

CD OO

O O

Test connection Dose mq / kg
Carcasses
weight Meet
route Percentage reduction in
medium worm load 17. late k ~ { 2-Aminoacetaraido) -3-
(3-inetho: cycarbonyl-2-thio-
ureido) diphenyl thioether
methanesulfonate " 10 SC H. contortus 51 h ~ (2-aminoacetemido) -3-
(3-etho :: ycarfoonyl-2-
thioureido) diphenyl
thioether 10 orally kk h- (2-Ajrninoacetamido) -3-
(3-etho; cycarbonyl-2-
thioureido) diphenyl thioether
methanesulfonate 10 SC 100 ho 3- (3-methoxycarbonyl-2-
thioureido- "i} - [2 ~ (N-methyl-
amino) acetamido] diphenyl—
thioätlier methanesulfonate ' 10 ■ se 100 50 3- (2- Atninoacetaraido) - k-
(3-methoxycarbonyl-2-
thioureido) diphenyl thioether
rnethan sulfonate · · 10 SC 98 75 100 100

IO

K) CD

Table IV (continued)

σ> ο co co co

ο ο c *>

Test compound; Dose mg / kg
Carcass
.weight Meet
route Percentage reduction in
medium worm load N, sOathiger fy- (2-aminoacGteraido) -3-
(3-methoxycarbonyl-2-
thioureido) ~ k '-methy1-
diphenyl thio ether
metal sulfonate 10 SC H. contortus 39 h- (3-methoj: carbonyl-2-
thioureido) -3- (2-diraethyl-
arainoacetaraido j diphenyl-
ether hydrochloride, 10 SC 87 3- (3-M, ethoxycarbonyl-2-
thioureido ) ~ k ^l -methyl * - ^ -
(2-diraethylaminoacetainido) -
dipTienyl thioether
methanesulfonate 10 SC 100 50 k ~ (3 ~ metho3: carbonyl-2.-
thioureido) -3- (3-dimethyl-
aminopropionamido) diphenyl-
thioether metal sulfonate ' .10. SC 97 70 3- (2-m ethylaminoacetamido) -
^ i - (3 -rnetho2cy c arbony 1-2-thio
ureido) diphenyl ~ thio ether
methane sulfonate 10 SC 100 98 100

ro ro

K)

Cn

CD

Table IV (Porting)

O) O CO OO Ca>

Test connection Dose mg Ag
Carcass
consecrated Administration,
route Percentage reduction in
medium worm load N. later h- allyl thio-1- (3 ~ metho3cy ~
carbonyl-2-thioureido-2- (2-
diinethylaminoacetamido) -
benz olnnethansulfonat · 10 SC H. eontortus 73 3 - (2 -wire thy larainoacetaraido) -
h- (3-methoxycarbonyl-2-thio-
ur eido) diphenyl ether -
hydroc? 11orid 10 SC 100 Th i4-Benayltliio ~ l- (3-ynethoxy-
carbonyl-2-thioureido) -2-
(2-ditne tiiylaminoacetamido) -
benzene methanesulfonate. 10 SC 100 60 k- ( 3-MGtho3 "ycarbonyl-2-
thiouroido) -3- (2-dimethyl-
arriinopropiona'mido) diphenyl -
thio ether inethanesulfonate 10 SC 100 100 ifOyclopentylthio-l- (3-
met ho: cycar 3x> ny 1- 2 - thio -
ureido) -2- (i 2-diraethylatnino-
acetamido) ben20l-
methane sulfonate 10 SC 100 100 100 ·

Table V

σ * ο co οο co

Test ver
binding P.
0
R.
M. Dose mg / kg
Carcasses
weight Meet
route Age of
infection
at the Be
plot
(Days). Percentage reduction in the mean
.Worm loading. . circum- ajcei colubri- ■ E-
later P. B. H orally 7th
21 κ.
contortus cincta formio 95
91 Q M. 25th intra
muscular 7th
21 100
100 Qk
100 R. M. 25th SC 7th
21 100
100 100
100 100
100 100
100 49
97 S. M. • 25 SC 7th
21 100
100 100
100 100
100 100
100 67
72 C. k orally 7,
21 100
100 58
. 100 100
100 97
100 k2
6h C. 10 orally 7th
21 100
99 100
78 97
100 • 99
79 9h
100 C. 25th SC 7th
21 100
100 34
100 100
100 100
100 57
21 100
• 100 96
100 100
100 100
100 100
98 66
97 98
96

4s I

ro

CD

Table V (port setting)

OT ο co oo CO

O O UX

Test-
jyerbin-
manure P.
O
R.
M. Dose mg / kg
Carcasses
weight Administration
ohujlgsweg Age of
infection
in the
treatment
(Days) Percentage reduction in the mean
Worm load a.
circum- axei colubri- S. '
later rn 3 k orally 7th
21 S.
contortus cincta formis U M. 25th SC 7th
21 99
100 100
100 100
9 it 67
73 M. 25th SC 7th
21 100
100 100
98 100
100 100
9k 100
65 100
100 100
100 100
100 100
100 95
97 100
100

IO

K) cn

CO

D. Activity on mature and immature liver fluke in sheep

On the first day of the experiment, 4 sheep each with 300 metacercariae from Fasciola hepatica and on the 56th day the same four sheep each with a further 300 metacercariae from P. hepatica infected.

On the 70th day, 2 sheep (hereinafter referred to as S1 and S2 in Table VI) were given an oral dose of 100 mg / kg animal body weight on 4- (j5-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) contained in gelatin capsules -diphenyl thioether, while the other two sheep (in Table VI with S3 and labeled S4) remained untreated and as control animals were used.

On the 98th day of the experiment, all four sheep were killed and examined. For each sheep, the number of mature leeches in the bile ducts and the number of those remaining in the one were recorded Immature leeches present in part of the liver were determined and the gallbladder examined for the presence of eggs. The results are given in Table VI below.

The livers of control animals S3 and S4 were highly fibrous. The livers of the treated animals S1 and S2 showed signs of infection by leeches, but the scars healed well and the livers returned to normal when the sheep were killed.

eO9831 / 1003

Table VI '

co 00

. Sheep, ' treated animals
• S2 untreated animals Ah Number of mature flukes in the bile ducts Sl 0 S3 172 Number of immature leeches in that
remaining part of the liver 0 1 9h 35 Eggs in the gallbladder ■ ο absent 2k .present absent present

O O Ca *

K?

CC —J

Compounds of the formula I in which Z represents a group of the formula II (R, R ² , R, R, R, A and X ^& have the meaning given above) are particularly valuable as anthelmintics due to their solubility in water, especially those compounds in which X® represents a chloride or methanesulfonate ion.

Another class of particularly useful anthelmintic compounds of the formula I are those in which R is a methyl group, R is a group of the formulas -SR, -SOR ^ or -OR ^ (where Br is a straight or branched chain alkyl group with 2 to 4 Carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a benzyl group or a phenyl group), A is a methylene - [- CH ₀ -] -, A'thylen-

[-CH ₀ CH ₀ -] - or ethylidene - [- CH (CH,) -] - group and

6 7 Z denotes a group of the formula II or IH, in which R and R each represent a hydrogen atom or a straight- or branched-chain alkyl group with 1 to J5 carbon atoms and in the formula II (if present) R ^ denotes a hydrogen atom and x? denotes a halide (eg bromide, iodide or preferably chloride) ion or methanesulfonate ion.

A class of compounds of the formula I which are particularly valuable as anthelmintics are those in which R is a

Represents a methyl group, R is a phenylthio or cyclopentylthio

group, A represents a methylene, ethylene or ethylidene group and Z represents a group of the formulas II or III, in which R and R 'each represent methyl groups and in .Formel II (if present) Br is a hydrogen atom and 3® Means chloride or methanesulfonate ion.

Of particular importance as an anthelmintic is 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenylthioether and its pharmaceutically acceptable salts.

€ 09831/1003

Apart from possessing an anthelmintic activity, the new compounds of general formula I are also useful as pesticides useful in agriculture, particularly as fungicides against species of fungi pathogenic to plants are and they also have effectiveness as fungicides against species of fungi that are pathogenic to animals.

For example, the compounds of the formula I can be used in particular in the case of fungicidal seed dressings, e.g. seed dressings to protect grain seeds, and especially useful for combating gray mold (e.g. Botrytis spp.) and brown mold and storage rot of fruits and vegetables, for example grapes, peaches, lettuce and beans.

As fungicides for use on species of opposite plants pathogenic fungi, the compounds of the formula I are particularly useful in the control of Alternaria solani, Botrytis cinerea, Cercospora beticola, Cochliobolus sativus, Colletotrichum spp., e.g. C. gassypii, Fusarium spp., e.g. F. nivalae and F. roseum, Gloeosporium spp., Helminthosporium spp., E.g. H. avenae and H. gramineum, Mycosphaerella spp., E.g. M. pinodes and M. pomi, Nectria spp., Penicillium spp., Piricularia orycae, Pythium spp., Rhizoctonia spp., Rhizopus nigricans, Sclerotinia spp., e.g. S. cinerea and S. sclerotiorum, Septoria nodurum, Tilletia caries, Ustilago avenae, Venturia inaegualis and Verticillium spp., e.g. V. alboatrum.

The fungicidal properties of the compounds of the formula I against plant-pathogenic fungi have been described, for example, in shown in the following test:

Inhibition of fungi growth on agar - in vitro

Three species of fungi were used: kept on:

Botrytis cinerea (spores) - potato dextrose agar

Helminthosporium avenae - oatmeal agar, in one

(mycelium) Czapek-Dox-Broth for Her

position of a mycelium sus-

609831/100 3 ^ft

25.4 3417

Mycosphaerella pinodes (spores) - Coon's agar.

All species were grown on fresh intermediate culture media in Grown at one week intervals.

Manufacture of fungi suspensions

Spore suspensions were made by using agar gradients (or concentrations) of one to two week old fungi cultures scratched with sterile distilled water using a glass rod. The cultures were then made by muslin filtered and the filtrate containing the spores used for inoculation.

H. avenae inoculum was prepared by growing a two week old liquid culture to give a fine suspension macerated.

Preparation of the suspensions of the test compound

0.025 g of test compound were ground with sterile distilled water [containing approx. 1.0 ml of a 0.1 % weight / volume solution of a wetting agent (Texofor Fx I70) in sterile distilled water] with a "Teflon" block and the The resulting suspension was made up to a volume of 50 ml with sterile distilled water. Portions of this suspension containing 500 parts per million by weight (ppm) of test compound were then serially diluted with sterile distilled water to give suspensions of 100 ppm and 20 ppm, respectively.

Test procedure

There were 4.0 ml of melted potato dextrose agar from Test tubes containing approx. 50 C with 0.5 ml of the test compound suspension of 500 ppm, 100 ppm or 20 ppm and 0.5 ml of the fungi suspension applied with a sterile syringe to obtain a Final test compound concentrations of 50 ppm, 10 ppm and 2 ppm, respectively

609831/1003

were introduced, vaccinated. Two analog test tubes of each Test compound concentrations were inoculated with each species of fungi. Analog test tubes without the one effective against fungi Means were also made in an analogous manner with the fungi suspensions vaccinated. After inoculating the molten agar, the test tubes were tilted and the agar allowed to settle. The test tubes were then incubated at 25 ° C for either 2 days (B. cinerea and M. pinodes) or 15 days (H. avenae). For each test compound, the minimum effective concentration (MEC) against each fungi species was given in terms of concentration determined at the two-thirds inhibition of the fungi growth compared to the control test tubes, the potato dextrose agar and fungi suspension alone was obtained. The results are shown in Table VII below specified.

Table VII

Test connection MEC (ppm of test ver
binding in agar 4- (3-methoxycarbonyl-2-thioureido) -
3— (2 -dime thy laminoacetamido) diphenyl-
thiaether Β _β cinerea (spores)> 50
H. avenae (mycelium) <2
M. pinodes (spores)> 50 4- (2-aminoacetamido) -3- (3-methoxy
carbonyl-2-thioureido) diphenyl-
thioether B. cinerea 10-50
H. avenae 2-10
M. pinodes 10-50 4- (3-methoxycarbonyl-2-thioureido) -
3- (3-dimethylaminopropionamido) -
diphenyl thioether B. cinerea 2-10
H. avenae <2
M. pinodes 10-50

603831/100 3

The symbol ">" in the table above means "greater than" and the symbol ^U 4J * means "less than".

The compounds of the formula I in which Z is a group of the formula II means (R, R, R, R, R, A and X have the meanings given above), are due to their solubility in water particularly valued as agents effective against fungi, in particular those compounds in which 3iP is a chloride or Is methanesulfonate ion.

Another class of compounds of the formula I which are particularly valued as active agents against fungi are those

1 2

in which R represents a methyl or ethyl group, R a

Phenylthio group and Z a group of the formula II darts 6 7
represents, wherein R ^, R and R each represent a hydrogen atom or a methyl group and x® represents a halide (eg chloride, bromide or iodide) ion or a methanesulfonate ion or of the formula III, wherein R and R 'each represent a hydrogen atom or a methyl group.

Another feature of the present invention is compounds of the general formula I prepared by suitable applications of known methods, e.g .:

1.) by reacting equimolecular amounts of an isothiocyanate of the general formula

SCNCO ₂ R ¹ IV

(wherein R is as defined above) and an amine of the general formula

SHCOAS

9 8 31/10 0 3

(in which R ² and A are as defined above and Z is a group of the formula II, in which R and R are as defined above and R- ^ is a hydrogen atom and X ^{& is} a halide ion, or of the formula III as defined above ) while achieving a connection of the

1 p
Formula I in which R, R and A are as defined above and Z is the group Z as defined above (hereinafter referred to as "compounds of the formula Ia").

. The reaction can be carried out in the presence of an inert solvent, e.g. a lower alkanone, e.g. acetone or methyl ethyl ketone, a lower alkanol, ζ.Β methanol or ethanol, dioxane, ethyl acetate, acetonitrile or an aromatic hydrocarbon, e.g. toluene, at a temperature between 0 ⁰ C and 150 ⁰ C and preferably between 10 ⁰ C and 6o ° C and optionally in the presence of acetic acid.

The isothiocyanates of the formula IV can be prepared by reacting an ester of the general formula

X ¹ CO ₂ R ¹ _VI

are prepared (where R has the meaning given above and X represents a bromine, iodine or preferably chlorine atom) and a thiocyanate of the general formula

(NCS) _q M VII

wherein M represents a metal, preferably an alkali metal or an alkaline earth metal atom, and q denotes the valence of the metal. The reaction may be in the presence of an inert organic solvent, for example a low alkanone, for example acetone, ethyl acetate or acetonitrile, at a temperature between 0 ⁰ C and 100 ⁰ C and preferably between 20 ° C and 6o ° C.

609831/1003

The preparation of the compounds of the formula IV can be carried out in situ for the subsequent reaction with compounds of the formula V be carried out or, if desired, the compounds of the formula IV by known methods before the reaction with Compounds of the formula V are isolated.

2.) By reacting an amine of the general formula

! CSNHCOOR ¹

VIII

1 2
(in which R and R have the meanings given above)

with a compound of the general formula

X ¹ COAZ ² IX

(where X and A are as defined above

p 1

and Z is a group Z as defined above, wherein However, neither R nor R 'can represent a hydrogen atom)

1 2 to obtain a compound of the formula I in which R _1, R and A are as defined above and Z is the group Z ² defined above, hereinafter referred to as "compounds of the formula Ib". The reaction is preferably carried out in an organic solvent, for example toluene or dimethylformamide, at a temperature between 0 ° C. and the reflux temperature of the reaction mixture.

The compounds of the formula IX can be prepared by reacting a compound of the general formula

HOOCAZ ² X

(where A and Z have the meanings given above) with a reactive acid halide such as phosphorus pentachloride. If desired, the connections of formula IX can be prepared in situ.

609831/1003

25.) by reacting an amine of the general formula VIII with a compound of the formula X (in which A and Z have the meanings given above) in the presence of a condensate, for example phosphorus oxychloride, in a suitable solvent, for example dimethylformamide or dichloromethane, at a temperature between O ⁰ C and the reflux temperature of the reaction mixture, obtaining a compound of the formula Ib.

4.) by reacting a compound of the general formula

[CSNHCOOR ¹

XI

12 1
(wherein R, R, A and X have the meanings given above

own) with

(a) a compound of the general formula

HHR ⁶ R ⁷ XII

(wherein R and R 'are as defined above), an excess of which is used as an acid-binding agent can be, to obtain a compound of the formula Ia, or

(b) a compound of the general formula

NR ⁵ R ⁶ R ⁷ XIII

6 7
(where R and R 'are as defined above and R · ^ is a straight or branched chain alkyl group having not more than 4 carbon atoms) to achieve a

1 2

A compound of the formula I in which R, R and A have the meanings given above and Z is a group of the formula II in which B? a straight or branched chain alkyl group

609831/1

- 356 -

6 represents 7 with no more than 4 carbon atoms, R and R 'the Have the meaning given above and the anion X ^ a Halide ion is derived from the halogen atom represented by X in the compound of formula XI.

The reaction between the compound of the formula XI and the compound of the formula XII can be carried out in an inert organic solvent, for example a lower alkanol, for example ethanol, or an aromatic hydrocarbon, for example benzene or toluene, at a temperature between 20 ^° C. and 100 ^° C. , preferably at room temperature or the reflux temperature of the reaction mixture.

The reaction between the compound of formula XI and the compound of formula XIII can be an organic solvent are carried out in the presence of, for example from ethyl acetate or diethyl ether, at a temperature between 20 ⁰ C and 8o ° C and preferably at the reflux temperature of the reaction mixture.

1 P 5.) by reaction of a compound of the formula I in which R, R and A are as defined above and Z is a Group of formula III represents (wherein R and R are the above have given meaning) with a compound of the general formula

R 2

(where R is as defined above and X

represents an atom or a group corresponding to the anion X ^)

to obtain a compound of the formula I wherein R, R and A are as defined above and Z is a group

¹ S f> 7 of the formula II, in which R, R and R 'have the meaning given above and the anion X ⁰ is derived from the atom or the group represented by the symbol X ² in the compound of the formula XIV. the reaction is preferably carried out in an inert organic solvent, for example ethanol, ethyl acetate, acetone or Diäthylather at a temperature between 10 ⁰ C and 40 ⁰ C.

60383 1/1003

2b4üAl 7

- 37 - 6.) by reacting a compound of the general formula

^. JiTHCSNHCOOR ¹ [COANR ⁶ R ⁸

12 6
wherein A, R, R and R are as defined above

and R represents a suitable protecting group, e.g. the benzyloxycarbonyl group, with a reagent for removal this protective group, e.g. a solution of hydrogen bromide in glacial acetic acid, to obtain a compound of the formula I, wherein R (in the definition of Z) represents a hydrogen atom, where the various other symbols have the meanings given above.

7.) by treating a compound of the formula I in which Z represents a group of the formula II in which R ^ is a hydrogen atom means (R, R, R, R, A and XP have the above given meaning) with a base to achieve a

1 2

Bond of the formula I, in which R, R and A have the meanings given above and Z represents a group of the formula III.

The reaction is preferably carried out with the aid of an alkali metal carbonate or hydroxide in the presence of water, generally carried out at room temperature and can optionally in situ without isolating the compound of the formula I, in which Z represents a group of the formula II, from the reaction mixture, in which it is formed by one of the reactions described above.

Compounds of the formula V can be obtained by reducing compounds of the general formula

609831/1003

2649417

XVI

[COAZ ¹

(in which R, A and Z have the meanings given above) by methods known for the reduction of aromatic nitro groups to amino groups, e.g. by hydrogenation in the presence of a Hydrogenation catalyst, e.g. platinum or palladium, or by using perchloride and reduced iron powder will.

Compounds of the formula XVI can by reacting a compound the general formula

XVII

NHCOi

ρ 1

(wherein R, A and X are as defined above) with a compound of the formula XII, of which an excess as acid binding agent can be used among those above for the reaction of compounds of formula XI with compounds of the formula XII described conditions are produced.

Compounds of the formula XVII can by reaction of a compound the general formula

XVIII

(wherein R has the meaning given above) with a compound of the general formula

609831/1003

X ¹ COAX ¹ XIX

where A and X have the meaning given above,) are prepared. The reaction is preferably a low alkanone, for example acetone, or an aromatic hydrocarbon, eg toluene, carried out in an inert organic solvent, for example at a temperature between ⁰ ° C and 11O ° C.

2 1 Compounds of the formula V, in which R, A and Z have the meanings given above, can be selected from compounds of the general formula

XX

Pl
(wherein R, A and X are as defined above) using the methods described above for the preparation of compounds of formula I from compounds of formula XI.

Compounds of the formula XX can be obtained by reducing compounds of formula XVII by methods known for the reduction of aromatic nitro groups, e.g. as described above for the Reduction of compounds of the general formula XVI have been described.

Compounds of the formula XI can be prepared by reacting a compound of the formula XX with an isothiocyanate of the formula IV will. The reaction can be carried out among the above for the reaction of the compounds of the formula IV with compounds of the Formula V can be carried out to achieve compounds of the formula I described conditions.

609831/1003

- * o - 2b494 17

Alternatively, compounds of the formula XI can be prepared by reacting a compound of the formula VIII with a compound of the formula XIX be established. The reaction can be carried out among those above for the reaction of compounds of formula XVIII with compounds of the formula XIX can be carried out to obtain compounds of the formula XVII described conditions.

Compounds of formula XV can be prepared:

(a) by reacting an amine of formula VIII with a compound the general formula

X ¹ COANr ^ - xxi

\ _R 6

wherein A, R, R and X have the meanings given above. The reaction is preferably carried out in an organic solvent, for example dimethylformamide, at a temperature between 0 ° <
guided.

See O ⁰ C and the reflux temperature of the reaction mixture through compounds of the formula XXI can be obtained by reacting a compound of the general formula

HOOCAlT

6 8

(where A, R and R have the meanings given above) with a reactive acid halide, e.g. phosphorus pentachloride, getting produced.

(b) by reacting an amine of the formula VIII with a compound of the formula XXII in the presence of phosphorus oxychloride in a suitable solvent, for example dimethylformamide, at a temperature between ⁰ ° C. and the reflux temperature of the reaction mixture.

6098 31/10 0 3

(c) by reacting a compound of the general formula

XXIII

COANR ⁶ R ⁸

ο (\ P
(wherein A, R, R and R are as defined above) with a compound of the formula IV by the methods described above for the preparation of compounds of the formula I from amines of the formula V.

Compounds of the formula XXIII can be prepared by reducing compounds of the formula

XXIV

NHCOANR ⁶ R ⁸

P f \ Pk
(in which A, R, R and R have the meanings given above) by methods known for the reduction of aromatic nitro groups to amino groups, for example by using ferrochloride and reduced iron powder.

Compounds of the formula XXIV can by reaction of compounds of the formula XVIII with compounds of the formula XXI or XXII for the preparation of compounds of the formula XV methods described are produced.

Under the term "known methods" as used here methods are to be understood that have previously been used or described in the chemical literature.

The following examples illustrate the preparation of the new compounds according to the invention.

609831/1003

example 1

A solution of 6.4 g of 4-amino-3- (2-dimethylaminoacetamido) diphenyl thioether in 100 ml of dry acetone is stirred while 2.7 g of methoxycarbonyl isothiocyanate are added dropwise, the temperature being reduced by external cooling between 15 ° C and 20 ° C and thereafter at the same temperature for an additional 20 minutes. The solution was concentrated in vacuo to give a yellow oil which was treated with diethyl ether. The solid product was obtained in the form of a pale buff solid (with a melting point of 143 - 144 ⁰ C) recrystallized from isopropanol with decomposition.

The 4-amino-j5- (2-dimethylamineacetamido) -diphenylthioether used as starting material was made as follows:

44 g of thiophenol was added over a period of 5 minutes under an atmosphere of dry nitrogen to a suspension of 66.5 g of 5-chloro-2-nitroaniline (prepared according to Fuson et al, J. Org. Chem., £, 799 -806, 1947) and 6o.6 g of anhydrous potassium carbonate in 200 ml of dimethylformamide. The reaction mixture was refluxed for 8 hours and then cooled. 200 ml of water were added dropwise while the temperature was kept at 5 to 10 ^° C. The precipitated solid was filtered off, washed well with water and from propanol to obtain 83 g of 3-amino-4-nitro-diphenylthioäther having a melting point of 117 - recrystallized a pale brown solid 118 ⁰ C in shape.

6.2 g of chloroacetyl chloride were added to a stirred solution of 12.3 g of 3-amino-4-nitro-diphenyl thioether in 50 ml of dry toluene were added. The solution was refluxed for 1 hour . The hot solution was added to 80 ml of petroleum ether (boiling point 60-80 ° C.), whereupon 15.8 g of 3- (2-Chloraeetamido) -4-nitro-diphenyl-thioether crystallized in the form of a yellow solid with a melting point of 152-154 ° C.

609831/1003

60 ml of a 33 % w / v solution of dimethylamine in ethanol were added to a suspension of 15 * 5 g of 3- (2-chloroacetamido) -4-nitrodiphenyl thioether in 14o ml of ethanol. The suspension was stirred and refluxed for 1 hour. The cooled solution was concentrated in vacuo to give a yellow solid. The pesticide was washed with 10 ml of ice-cold ethanol and then suspended in 100 ml of water. The solid was filtered off, washed with water and dried at 80 ° C. to obtain 14.9 g of 3- (2-dimethylaminoacetamido) -4-nitrodiphenylthioether.

One added to a solution of 14.9 g of 3- (2-dimethylaminoacetamido) -4-nitrodiphenyl thioether in 200 ml of ethyl acetate β g of a palladium-activated carbon catalyst (5 % palladium w / w). The suspension was shaken in a hydrogen atmosphere at atmospheric pressure and room temperature.

After 90 minutes 3 * 1 liter of hydrogen has been absorbed. the Solution was filtered and in vacuo to give 12.9 g of 4-amino-3- (2-dimethylaminoacetamido) diphenyl thioether in the form of a white solid with a melting point of I3I - 133 ° C concentrated.

Example 2

7.9 g of 4-amino-3- (3-methoxycarbonyl-2-thioureido) diphenyl thioether were added to a stirred solution in 50 ml of dimethylformamide 3 * 8 g of NjN-dimethylglycyl chloride hydrochloride for 5 minutes. The reaction temperature rose to 37 ° C. during the addition and a white solid began to separate out. The reaction mixture was then stirred and heated to 40-45 ° C. for 75 minutes, cooled and diluted with 150 ml of acetone. The solid was collected on a filter, washed with acetone and sucked dry. The solid was in a boiling mixture 100 ml of methanol and 10 ml of water were dissolved and the solution was treated with decolorizing charcoal and filtered hot. They were left to obtain 5.25 g of 3- (3-methoxycarbonyl-2-thioureido) -4- (2-dimethylaminoacetamido) diphenyl thioether hydrochloride in the form of a white crystalline solid with a melting point

609831/1003

193 ⁰ C to crystallize out (with decomposition) - of I92.

The 4-amino -> - (j5 "- methoxycarbonyl-2-thioureido) -diphenyl-thioether used as starting material was made as follows:

12 g of methoxycarbonyl isothiocyanate were added dropwise during 5 minutes to a stirred solution of 12.3 g of 3-amino-4-nitrodiphenyl thioether (prepared as described above in Example 1) in 90 ml of acetonitrile. The reaction temperature was kept at 15-20 ° C. by external cooling during the addition. The mixture was then heated to 40-45 ° C and stirred for a further 5 hours, a yellow solid taking leave. The reaction mixture was cooled in ice and filtered. The residue was washed with diethyl ether and dried, 12.9 g of 3- (3-methoxycarbonyl-2-thioureido) -4-nitrodiphenyl thioether with a melting point of 144-145 C (with decomposition) were obtained.

11.1 g of reduced iron powder was partially over 5 minutes to form a rapidly stirred mixture of 12.1 g of 3> - (3-methoxycarbonyl-2-thioureido) -4-nitrodiphenyl thioether and 2.2 g of ferrochloride tetrahydrate in 167 ml Methanol and J> 1 ml of water heated to reflux temperature were added. After 90 minutes the black suspension was diluted with 150 ml of methanol, filtered hot through a Hyflo bed and the Hyflo bed was washed twice with hot methanol (2 × 50 ml). The combined solution was heated again, treated with decolorizing charcoal, filtered hot and then concentrated to about half its volume under reduced pressure. The whitish solid which separated out was filtered after cooling, sucked dry on the filter and extracted from a mixture of 450 ml of methanol and 250 ml of water to give 8.1 g of 4-amino-3 - (^ - methoxycarbonyl-2-thioureido) -diphenyl -thioether with a melting point of 164-165 ⁰ C recrystallized.

809831/1003

Example 3

A solution of 1.0 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether was treated (prepared as described in Example 1 above) in a minimal volume of acetone with an excess of saturated Solution of hydrogen chloride in anhydrous diethyl ether. Of the rapidly crystallizing solid was filtered off and extracted from ethanol to obtain 0.7 g of 4- (3-methoxyearbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -dipheny1-thioether hydrochloride with a melting point of 194 - 195 ° C (with decomposition) recrystallized.

Example 4

A solution of 5 * 0 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -dipheny1-thioether (prepared as described in Example 1) in 80 ml of acetone was treated with a solution of 1, 2 g methanesulfonic acid in 20 ml acetone. After allowing the mixture to stand for 30 minutes, the precipitated pesticide was filtered off and crystallized from ethanol to give 4.2 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether methanesulfonate with a melting point of I69 ■ - 171 ⁰ C (with decomposition).

Example 5

A solution of 1.25 g of 4- (3-methoxyearbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -dipheny1-thioether (prepared as described above in Example 1) in JO ml of acetone was treated with shaking at 0, 35 g maleic acid. The pest dissolved quickly and the mixture was left to stand overnight. The obtained pesticide was filtered off, washed with 10 ml of cold acetone and extracted from ethanol to give 0.8 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether maleate having a melting point 123 ⁰ C recrystallized (with decomposition) - of the 121st

Θ09831 / 1003

Example 6

The procedure was analogous to that described in Example 2, except that the 4-amino-3- (3-methoxycarbonyl-2-thioureido) -diphenyl-thioether used as starting material was replaced by suitable amounts of 4-amino-4 ^f - ehlor-JO-methoxycarbonyl-2-thioureido) -diphenyl-thioether,

4-Amino-3- (3-methoxycarbonyl-2-thioureido) -4'-methyldiphenylthioether,

3-amino-4- (3-methoxycarbonyl-2-thioureido) diphenyl ether,

2-Amino-1- (3-methoxycarbonyl-2-thioureido) -4-methylthiobenzene or, 4-allylthio-2-amino-1- (3-methoxycarbonyl-2-thioureido) benzene,

and made the following connections:

4 '-Chlor-3- (3-methoxycarbonyl-2-thioureido) -4- (2-dimethylaminoacet-amido) -diphenyl-thioether-hydrochloride, Melting point 183 185 ° C (with decomposition),

3- (3-Methoxycarbonyl-2-thioureido) -4 ^f -methyl-4- (2-dimethylaminoacetamido) -diphenyl-thioether hydrochloride, melting point 18-184 C (with decomposition),

4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl ether hydrochloride, melting point 164-165 ⁰ C (with decomposition)

l- (3-methoxycarbonyl-2-thioureido) -4-methylthio-2- (2-dimethylaminoacetamido) benzene hydrochloride, melting point 166-167 ⁰ C and

4-Allylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene hydrochloride, Melting point 177 - 178 ° C (with decomposition).

The starting materials were prepared as follows:

(a) by proceeding in a manner analogous to that in Example above 2, but the one used as the starting material

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3- (3-Methoxycarbony1-2-thioureido) -4-nitrodiphenyl thioether replaced by appropriate amounts of

4 '-Chlort- (3-methoxyearbony 1-2-thioureido) -4-nitrodiphenylthioether,

3- (3-Methoxycarbonyl ~ 2-thioureido) -4 ¹ -methyl-4-nitrodiphenylthioether,

4- (3-Methoxycarbony1-2-thioureido) -3-nitrodiphenyl ether,

l- (3r-methoxycarbonyl-2-thioureido) -4-methylthio-2-nitrobenzene or 4-allylthio-1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene,

the following connections were established:

4-amino-4'-chloro-3- (3-methoxycarbonyl-2-thioureido) -diphenylthioäther, m.p. ^162-0

4-Amino-3- (3-methoxyearbony1-2-thioureido) -4 ^! methyldiphenylthioether, melting point 143-145 ° C,. '·

3-Amino-4- (3-ynethoxy carbony 1-2-thioureido) -dipheny lather, Melting point 184 - 186 ° C (with decomposition),

2-Amino-1- (3-methoxycarbony1-2-thioureido) -4-methylthiobenzene, mp 167-169 ⁰ C and

4-Allylthio-2-araino-l- (3-niethoxycar bony 1-2-thioureido) benzene, melting point 164-165 ⁰ C (with decomposition).

(b) 39/3 ml of methyl chloroformate was added in one portion to a stirred suspension of 43.4 g of dry potassium thiocyanate in 540 ml of acetonitrile and the mixture was stirred for one hour at room temperature. There were 42.4 g of 3-amino-4'-chloro-4-nitro-diphenyl-thioether added and the mixture was stirred at room temperature for 2 hours and then for 3 hours at 4o - stirred 50 ⁰ C. The mixture was then poured into 2 l water and the solid which formed was filtered off and extracted from a mixture of ethanol and dimethylformamide to give 42.3 g of 4'-chloro-3- (3-methoxycarbony1-2-thioureido) -

60983 1/100 3

4-nitrodiphenyl thioether with a melting point of 169 ⁰ C (with decomposition) recrystallized.

The procedure was analogous, but the 3-amino-4'-chloro-4-nitrodiphenyl thioether was replaced by appropriate amounts of

3-amino-4'-methyl-4-nitrodiphenyl thioether,

4-amino-3-nitro-dipheny1-ether,

4-methylthio-2-nitroaniline or

4-allylthio-2-nitroaniline

and made the following connections:

J5 (3-methoxycarbonyl-2-thioureido) -4 '-methyl-4-nitrodiphenylthioäther, mp 148-150 ⁰ C (with decomposition)

4- (j5-Methoxy car bony l-2-thioureido) -3-nitrodipheny 1-ether, Melting point I38 - 14o ° C,

1- (5-methoxycarbonyl-2-thioureido) -4-methylthio-2-nitrobenzene, melting point 152-154 ⁰ C and

4-allylthio-1- (j5-methoxycarbonyl-2-thioureido) -2-nitrobenzene, Melting point 121-123 ° C.

(c) (i) The procedure was analogous to that described above in Example 1, but the one used as the starting material was replaced Thiophenol with suitable amounts of 4-chlorothiophenol or 4-methyl- (thiophenol) and presented the

3-Amino-4'-chloro-4-nitro-diphenyl-thioether, melting point 118 120 ⁰ C and

3-amino-4 ^! -methyl-4-nitro-diphenyl-thioether, melting point 103104 ° C.

(ii) A stirred mixture of 38 g of 4-acetamido-3-nitrodiphenyl ether was heated (prepared as described in J.A.C.S. 68, 1548 (1946)), 57 ml of water and 75 ml of conc. sulfuric acid under reflux for 5 minutes. The mixture was then

609831/1003

cooled, poured into 500 ml of ice water and added by made alkaline with concentrated aqueous ammonia solution. The mixture was extracted with 3 x 400 ml of chloroform, the The extract was dried over magnesium sulfate and obtained 28 g of 4-amino-3-nitro-diphenyl ether in the form of a red Oil that was used in the next step without further purification, evaporated.

(iii) 17.6 g of 2-nitro-4-thiocyanato-aniline were added in portions added to a stirred solution of 13.4 g of potassium hydroxide in 210 ml of ethanol cooled to a temperature below 15 ° C. After 5 minutes, 12.8 g of methyl iodide became the purple Solution was added and the mixture was allowed to stand at room temperature overnight. The mixture was then in 1100 ml Poured water and filtered off the deep red pest, washed with water and obtained 15.8 g of 4-methylthio-2-nitroaniline dried with a melting point of 72-73 ° C.

The procedure was analogous, but this was replaced as the starting material used methyl iodide by the appropriate amount of allyl bromide and thus produced 4-allylthio-2-nitroaniline in the form of a red oil.

(d) A stirred mixture of 82.5 g of o-nitroaniline, 180 g of dry sodium thiocyanate and 1 liter of acetic acid was treated at 11-12 ° C. with a solution of 96 > 5 g of bromine in 100 ml of acetic acid. Stirring was continued for an additional hour at 11-12 ° C. The mixture was allowed to warm to 15 ° C. and poured into 3.5 liters of water. The yellow solid was filtered off, washed with water and dissolved in 1 l of acetone. The solution was filtered and the filtrate was evaporated to give 107 g of 2-nitro-4-thiocyanato-aniline with a melting point of 110-112 ° C.

Example 7

6.92 g of 3- (3-methoxycarbonyl-2-thioureido) -4 were suspended ^! - methyl-4- (2-dimethylaminoacetamido) -diphenyl-thioether-hydro-

6 09831/1003

Chloride (prepared as described in Example 6 above) in a mixture of 100 ml of water and 170 ml of chloroform the suspension with a solution of 1.57 g of sodium carbonate in 50 ml of water and stirred vigorously for 15 minutes. the organic layer was separated and the aqueous layer was extracted with 100 ml of chloroform. The organic layers was combined, washed with water, dried over magnesium sulfate and evaporated. The oil obtained solidified on scratching and was converted from ethanol to give 3.7 g 2- (3-methoxycarbonyl-2-thioureido) -4'-methyl-4- (2-dimethylaminoacetamido) diphenyl thioether recrystallized with a melting point of 146 147 ° C (with decomposition).

The procedure was analogous, but this was replaced as the starting material used 3- (3-methoxycarbonyl-2-thioureido) -4'-methyl-4- (2-dimethylaminoacetamido) diphenyl thioether hydrochloride by the appropriate amount of

3- (3> -Me thoxy car bony 1-2- thio ureid ο) -4- (2 -dime thy laminoac etamido) diphenyl thioether hydrochloride (prepared as described above in Example 2),

4 ¹ -Chlor ~ 3- (3-methoxycarbonyl-2-thioureido) -4- (2-dimethylaminoacetamido) -diphenyl-thioether hydrochloride (prepared as described above in Example β),

4- (3-Methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl ether hydrochloride (prepared as described above in example β),

1- (3-Methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) -4-methylthiobenzene hydrochloride (prepared as described above in Example 6) or

4-Allylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene hydrochloride (prepared as described above in Example 6)

and made the following connections:

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3- (3-methoxycarbonyl-2-thioureido) -4- (2-dimethylaminoacetamido) diphenyl thioether, mp 149-150 ⁰ C (with decomposition)

4 ¹ ~ chloro-3- (3-methoxycarbonyl-2-thioureido) -4- (2-dimethylaminoacetamido) diphenyl thioether, melting point 170-172 ⁰ C,

4- (3-methoxycarbonyl-2-thioureido) -j5- (2-dimethylaminoacetamido) diphenyl ether, Melting point 159 - 16l ° C (with decomposition),

l- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) -4-methylthiobenzene, Melting point 142-145 ° C (with decomposition) and

4-Allylthio-l- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene, melting point 133-134 ⁰ C (with decomposition).

Example 8

A stirred solution of 8.35 g of 2-amino-4-ethylthio-1- (3-methoxycarbonyl-2-thioureido) benzene in βθ ml of dimethylformamide was treated at room temperature with 5-53 g of Ν, Ν-DImethylglycylchloride hydrochloride. The mixture was for 45 minutes at 40 - 50 ⁰ C is heated, then cooled and diluted with 900 ml Diäthylather. An oil separated out which crystallized out on standing. The solid was filtered off, washed with 100 ml of diethyl ether and suspended in a mixture of 100 ml of chloroform and 100 ml of water. 3> 5 g of sodium carbonate were added and the mixture was stirred for 20 minutes. The chloroform layer was separated and the aqueous layer was extracted twice with 2 × 50 ml of chloroform. The organic layers were combined, dried over magnesium sulfate and evaporated to dryness. The remaining solid was recrystallized from isopropanol to obtain 8.5 g of 4-ethylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene with a melting point of 142 ° C. (with decomposition) .

The procedure was analogous, but this was replaced as the starting material used 2-amino-4-äthylthio-l- (3-methoxycarbonyl-2- ■ thloureido) benzene by suitable amounts of

609831/1003 *

2-amino-4-benzylthio-1- (j5-methoxycarbonyl-2-thioureido) benzene, 2-Amino-4-n-butylthio-1- (3-methoxycarbony1-2-thioureido) -benzene,

2-Amino-4-cyclopentylthio-1- (; 3-methoxycarbonyl-2-thioureido) benzene respectively.

2-Amino-4- (2-ethylthioethylthio) -1- (3-methoxycarbony1-2-thioureldo) benzene

and made the following connections: ■

4-Benzylthio-1- (3-niethoxycarbonyl-2-thioureido) -2- (2-dirnethylaminoacetamido) benzene, Melting point 115 - 116 C,

4-n-Butylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene, Melting point 1O4 - 1O6 ° C,

4-Cyclopentylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethyl-

aminoacetamic settlement) and

aminoacetamido) benzene, melting point 126 - 130 C (with decomposition

4- (2-Ethylthioäthylthio) -l- (3-methoxycarbonyl-2-thioureido) 2- (2-dimethylaminoacetamido) benzene, Melting point 86-87 ° C.

The starting materials were prepared as follows:

(a) A mixture of 14.0 g of 4-ethylthio-1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene, 0.04 g of ferrochloride tetrahydrate, 235 ml of methanol and 50 ml of water was refluxed and treated in part with 15 * 5 g of reduced iron powder for 5 minutes. The mixture was refluxed with stirring for one hour. 250 ml of methanol were added and the mixture was refluxed again. The hot mixture was filtered and the piltrate was allowed to cool to room temperature. The crystallizing upon cooling the solid was filtered off and yielded 7.5 g of 2-amino-4-ethylthio-l- • O-niethoxycarbonyl-2-thioureido) -benzene having a melting point 'of 168 ⁰ C.

609831/1003

The procedure was analogous, but this was replaced as the starting material 4-ethylthio-1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene used by appropriate amounts of

4-benzylthio-1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene, 4-n-Butylthio-1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene,

4-Cyclopentylthio-1- (; 5-methoxycarbonyl-2-thioureido) -2-nitrobenzene respectively.

4- (2-Ethylthioethylthio) -1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene

and made the following connections:

2-amino-4-benzylthio-1- (3-methoxycarbonyl-2-thioureido) benzene, Melting point 191 - 193 ° C,

2-amino-4-n-butylthio-1- (5-methoxycarbonyl-2-thioureido) benzene, Melting point 164 - 165 ° C,

2-amino-4-cyclopentylthio-l- (3-methoxycarbonyl-2-thioureido) benzene, m.p. I69 - 172 ⁰ C, and

2-Amino-4- (2-äthylthioäthylthio) -l- (3-methoxycarbonyl-2-thioureido) -benzene, Melting point 15I - 153 ° C.

(b) A mixture of 25 * 65 g of dry potassium thiocyanate and 320 ml of acetonitrile was cooled to 10 ^° C. and treated with 25 * 0 g of methyl chloroformate for 5 minutes. The mixture was stirred for 2 hours at room temperature. 22.45 g of 1-amino-4-ethylthio-2-nitrobenzene were then added to the mixture at 10.degree.-15.degree. The suspension was stirred at room temperature for 3 hours and left to stand overnight. It was then poured into 1.6 l of water and the precipitating pesticide was filtered off, washed with water and from a mixture of methanol and ethanol to give 14.0 g of 4-ethylthio-1- (3-methoxycarbonyl-2- thioureido) -2-nitrobenzene with a melting point of 152 ° C recrystallized.

€ 09831/1003

The procedure was analogous, but the 1-amino - ^ - ethylthio ^ -nitrobenzene used as starting material was replaced by suitable ones Sets of

l-Amino-4-benzylthio-2-nitrobenzene, 1- Amino ^ -n-butylthio ^ -nitrobenzene, l-Amino-ty-cyclopentylthio ^ -nitrobenzene or IrAmino -4- (2-ethylthioethylthio) -2-nitrobenzene

and made the following connections:

4-benzylthio-1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene, Melting point 172 - 174 ° C (with decomposition),

4-n-Butylthio-1- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene, Melting point 129 - 131 ° C,

4-Cyclopentylthio-1- (5-methoxycarbonyl-2-thioureido) -2-nitrobenzene, Melting point 125 C and

4- (2-Äthy lthioäthy lthio) -l- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene, melting point ^130-0

(c) 17.55 g of 2-nitro-4-thiocyanatoaniline (prepared as described above in Example 6) were added in part to a stirred solution of 13 * 4 g of potassium hydroxide in 210 ml of ethanol, the temperature being below 20 ⁰ C held. After 5 minutes, 14.4 g of ethyl iodide were added over 5 minutes. Stirring was continued for an additional hour and the mixture was allowed to cool overnight. The mixture was then poured into 1100 ml of water and extracted with 3 x 300 ml of chloroform. The chloroform layers were combined, washed with 500 ml of water, dried over magnesium sulfate and evaporated to give 17.0 g of 1-amino-4-ethylthio-2-nitrobenzene in the form of a red oil.

€ 09831/1003

By proceeding in an analogous manner, but using this as the starting material Ethyl iodide used by suitable amounts of benzyl bromide, n-butyl iodide, cyclopentyl bromide or 2-ethylthioethyl chloride replaced, the following connections were made:

l-Amino ^ -benzylthio ^ -nitrobenzene, melting point 97 - 99 ° C, l-Amino - ^ - n-butylthio ^ -nitrobenzene in the form of a red oil,

l-Amino ^ -eyclopentylthio ^ -nitrobenzene in the form of a brown - oils and

l-Amino-4- (2-äthylthioäthylthio) -2-nitrobenzene in the form of a red oil.

Example 9

A stirred solution of 0.5 g of 3-amino-4- (2-methoxycarbonyl.-2-thioureido) diphenyl sulfoxide was treated in 5 ml of dry Diineüiylfbrmamid at room temperature with 0.32 g of Ν, Ν-dimethylglycyl chloride hydrochloride. After 90 minutes the solution was poured into 50 ml of diethyl ether. The oil obtained solidified and the solid was filtered off and from a mixture of Methanol and diethyl ether to give 0.1 g of 4- (j5-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl sulfoxide hydrochloride with a melting point of 195 197 ° C recrystallized.

The j5-amino-4- (3-methoxycarbonyl-2-thioureido) diphenyl sulfoxide used as starting material was made as follows:

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24.8 g of 4-acetamidodiphenyl sulfide [prepared as described in Parmaco (Ed.Sei.) * M * ^2δ8-3 ° 3 ( ¹ ^)] were dissolved in 200 ml of ethanol and the solution was treated at 40-45 ° C with a hydrogen peroxide solution (100 volumes 23 ml). The mixture was then refluxed for β hours and an additional amount of hydrogen peroxide (7 ml) was added and refluxing continued for an additional 6 hours. The excess hydrogen peroxide was by adding 1 g of manganese dioxide and. Heating under reflux for 20 minutes destroyed. The solution was filtered and the filtrate was added to 1250 ml of water. The solid obtained was filtered off, 20.8 g of 4-acetamidodiphenyl sulfoxide having a melting point of I ² K) −142 ° C. being obtained.

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16.7 g of 4-acetamidodiphenyl sulfoxide were dissolved in a mixture of 10 ml of glacial acetic acid, 13 ml of acetic anhydride and 0.42 ml of concentrated sulfuric acid. The mixture was ^{cooled to 0 °} C. and 4.4 ml of 96% strength by weight nitric acid in 7 ml of glacial acetic acid were added dropwise with stirring. After the addition was complete, the solution ^{was stirred at 5-10 °} C. for 1 hour and then poured into water. The resulting oil crystallized on standing and the solid was filtered off and recrystallized from a mixture of ethanol and cyclohexane, with l4 g of 4-acetamido-3-nitrodiphenyl sulfoxide having a melting point 125-130 ⁰ C were obtained.

A mixture of 11.5 S 4-acetamido-3-nitrodiphenyl sulfoxide, 190 ml of methanol and 30 ml of an aqueous sodium hydroxide solution (50 % w / v) was stirred at room temperature for 10 minutes. The mixture was then poured into 1 liter of water and extracted with dichloromethane. The extract was washed with water, and dried over magnesium sulfate evaporated to give a yellow oil which was purified by trituration with petroleum (bp 6o - 80 ⁰ C.) Was solidified. The resulting solid was filtered to yield 9.1 g of 4-amino-3-nitrodiphenylsulfoxid having a melting point of l4o - 148 ⁰ C were obtained.

A solution of 1.0 g of 4-amino-3-nitrodiphenyl sulfoxide in 25 ml of acetone was treated with 2.5 ml of methoxycarbonyl isothiocyanate and the mixture was left to stand for 3 days. Another 1.0 ml amount of methoxycarbonyl isothiocyanate was added and the mixture was allowed to stand. The solid which slowly crystallized, was filtered off and recrystallized from a mixture of chloroform and methanol to give 0.9 g of 4- (3-methoxycarbonyl-2-thioureido) -3-nitrodiphenylsulfoxid having a melting point 197-199 ⁰ C ( with decomposition).

6098 3 1/1003

A mixture of 7.5 g of 4- (5-methoxycarbonyl-2-thioureido) -2-nitrodiphenyl sulfoxide, 1625 ml of methanol and 725 ml of water was refluxed. 75 grams of sodium dithionite was added and the mixture was refluxed until the yellow color had virtually completely disappeared (about 15 minutes). The mixture was cooled and poured into water. The mixture was extracted with chloroform, the extract dried over magnesium sulfate and concentrated to a small volume. Methanol was then added to the solution which was then allowed to cool. The resulting solid was filtered to yield 0.5 g of 5 ~ amino-4- (5-methoxycarbonyl-2-thioureido) diphenyl sulfoxide were obtained with a melting point of 183-185 ⁰ C.

Example 10

A mixture of 55, 5 g of methyl chloroformate, 35 6 dry potassium thiocyanate and 255 ml of ethyl acetate were stirred at 60 ⁰ C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was added over 5 minutes to a solution of 52 g of 4-amino-5- (2-dimethylaminoacetamido) diphenyl thioether ". (Prepared as described in Example 1) in 520 ml of glacial acetic acid, and the mixture was at Stirred at room temperature and then poured into 700 ml of ice water. The solution was neutralized to pH 7 by adding aqueous sodium hydroxide solution (50 # w / v.) The mixture was extracted with 3 × 400 ml of styl acetate, and the extract was dried over magnesium sulfate and evaporated to give a solid which was recrystallized from isopropanol, the 57.2 g of 4- (5-methoxycarbonyl-2-thioureido) -3- (2-dimethy1aminoacetamido) diphenyl thioether with a Melting point of 145-146 ⁰ C represents.

6 0 9,831 / 100 3

When working in the same way but replacing the 4-araino-3- (2-dimethylaminoacetamido) -diphenyl-thioether as starting material with suitable proportions of 4-amino-3- (2-pyrrolidin-l-ylacetamido) -diphenyl-thioether, 4-Amino-j5- (3-dimethylajninopropionamido) -diphenyl-thioether, 4-Amino-j5- (2-diethylaminoacetamido) -diphenyl-thioether, 4-amino-] 5- (2-dimethylaminoacetamido) -diphenylether, 4-amino -j5- (2-diethylaminoacetamido) diphenyl ether and 4-amino-3- (2-dimethylaminopropionamido) diphenyl thioether were obtained correspondingly 4- (3-methoxycarbonyl-2-thioureido) -3- (2-pyrrolidine-1- yl-acetamido) -diphenyl-thioether, m.p. 151-152 ⁰ C (with decomposition), 4- (5-methoxycarbonyl-2-thioureido) -; 5- (3-dimethylaminopropionamido) -diphenyl-thioether, m.p. 148 - 149 ⁰ C, 5- (2-diethylaminoacetamido) -4- (3-methoxycarbonyl-2-thioureido) -diphenyl-thioether, mp. 136-1J7 ⁰ C (with decomposition),

4 _r (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyläther, mp. 159 - 161 ⁰ C (with decomposition)

5- (2-Diäthylaminoacetamido) -4- (3-methoxycarbonyl-2-thioureido) -diphenyläther, mp 175 -. 176 ⁰ C (with decomposition) and 4- (3-methoxycarbonyl-2-thioureido) -5- (2 -dimethylaminopropionamido) diphenyl thioether, mp 157 -. 158 ⁰ C (with decomposition).

The starting materials were prepared as follows;

(a) A mixture of 14.7 g of 4-nitro-3- (2-pyrrolidin-1-yl-acetamido) -diphenyl-thioether, 200 ml of ethyl acetate and 5 g of a catalyst made from palladium on charcoal (5 % Pd W / w) was shaken in a hydrogen atmosphere under atmospheric pressure at room temperature until the absorption of hydrogen (about 3 liters) ceased.

609831/1003

- 6ο -

254Ü4 1

The mixture was then refluxed to dissolve about

crystallized material heated, filtered hot to remove the catalyst and allowed to cool at room temperature. The solid which was then crystallized, was filtered off to give 8.4 g of 4-amino-3- (2-pyrrolidin-l-ylacetamido) diphenyl-thioether having a melting point of 157 - 158 ⁰ C was obtained.

By working in the same way but replacing the 4-nitro-3- (2-pyrrolidin-1-ylacetamido) -diphenyl-thioether as starting material through the appropriate amounts of 3- (5HDimethylaminopropionamido) -4-nitrodiphenyl thioether, 3- (2-diethylaminoacetamido) -4-nitrodiphenyl-thioether, 3- (2-dimethylaminoacetamido) -4-nitrodiphenyl-ether, 3- (2-diethylaminoacetamido) -4-nitrodiphenyl ether and 5- (2-dimethylaminopropionamido) -4-nitrodiphenyl thioether were obtained accordingly

4-Amino-3- (3> -dimethylaminopropionamido) -diphenyl-thioether, m.p. 129 - IJO ⁰ C,

4-Amino-3- (2-diäthylaminoacetamido) diphenyl thioether mp. 76 - 78 ⁰ C,

4-Amino-3- (2-dimethylaminoacetamido) -diphenyläther mp. 121 - 123 ⁰ C,

4-Amino-3- (2-diäthylaminoacetamido) -diphenyläther mp. 83 - 85 ⁰ C and

4-Amino-3- (2-dimethylaminopropionamido) diphenyl thioether, isolated as the dihydrochloride, mp 163 -. 165 ⁰ C.

(b) (i) A stirred mixture of 26.0 g of 3- (2-chloroacetamido) -4-nitrodiphenyl thioether (prepared as described in Example 1), 11.5 g of pyrrolidine and 200 ml of ethanol was heated to reflux for 4 hours. The mixture was then allowed to cool and the product that crystallized

603831/1003 ORIGINAL INSPECTED

ized, filtered off, wherein l4,7 g of 4-nitro-J5 (2-pyrrolidinl-yl-acetamido) -diphenylthioäther having a melting point of 99 - 101 ⁰ C were obtained.

By working in the same way but replacing 5- (2-chloroacetamido) -4-nitrodiphenyl thioether and pyrrolidine as starting materials with corresponding amounts of 3- (j5-chloropropionamido) -4-nitrodiphenyl thioether and dimethylamine, 3- (3-dimethylaminopropionamido ) -4-nitrodlphenylthioether with a melting point of 65-67 ⁰ C produced.

If one worked again in the same way but replacing the 5- (2-chloroacetamido) -4-nitrodiphenylthioether and pyrrolidine as starting materials with corresponding amounts of 3- (2-chloroacetamido) -4-nitrodiphenyl ether and dimethylamine, then 3- (2 ~ dimethylaminoacetamido) -4-nitrodiphenyläther having a melting point of 119-120 ⁰ C.

(ii) A mixture of 11.0 g of 3- (2-chloroacetamido) -4-nitrodiphenylthioether (prepared as described in Example 1), 250 ml of dry toluene and 15 * 5 ml of diethylamine was heated under reflux for ΐβ hours. The mixture was then cooled and the diethylamine hydrochloride that crystallized was filtered off. The Flltrat was evaporated to give a brown oil which was purified in boiling petrol (b.p. 4o - 60 ⁰ C.) Was dissolved. The solution was cooled to room temperature and the resulting crystals were filtered off, whereby. -4-nitrodiphenylthioäther 9.9 φ- (2-Diäthylaminoacetamido) having a melting point of 57-58 ⁰ C were obtained.

When working in the same way, but replacing the 3- (2-chloroacetamido) -4-nitrodlphenylthioether as the starting material with corresponding amounts of 3- (2-chloroacetamido) -4-nitrodiphenyl ether, 2- (2-diethylaminoacetamido) -4-nitrodiphenyl ether was also used a melting point of II9 - 120 ⁰ C produced,

609831/100 3 ORIGINAL INSPECTED

2543417

(iii) 23.7 g of 5- (2-chloropropionamido) -4-nitrodiphenylthioether were dissolved in 100 ml of dry toluene and the solution treated with a solution of dimethylamine in toluene (45 g of 27% w / w). The mixture was heated on the water bath in a pressure bottle for 16 hours. The bottle was cooled and opened and the solution filtered to remove the dimethylamine hydrochloride. The filtrate was evaporated and the resulting yellow oil dissolved in ethyl acetate and treated with an excess of a solution of hydrogen chloride in diethyl ether. The resulting oil was solidified by scratching. The solid was filtered off to give 22.4 g of 3- (2-dimethylaminopropionamido) -4-nitrodiphenylthioätherhydrochlorid having a melting point 213-215 ⁰ C were obtained.

(c) A mixture of 12.3 g of I-amino - ^ - nitrodiphenylthioether, 7.6 g of I-chloropropionyl chloride and 50 ml of dry toluene was refluxed for 1 hour. The mixture was cooled to below 80 ⁰ C and then in 100 ml of gasoline - poured (bp 60 80 ⁰ C.). The precipitated solid was filtered, washed with 150 ml of cold petrol - washed and dried to give g J5 (3-chloropropionamido) -4-nitrodiphenylthioäther 16.1 having a melting point of 142 (bp 60 80 ⁰ C.) - 144 ⁰ C obtained became.

By working in a similar manner but substituting for j5-chloropropionyl chloride as a starting material by an appropriate amount of 2-chloropropionyl chloride was nitrodiphenylthioäther -4-having a melting point of 58 3- (2-chloropropionamido) - received 59 ⁰ C.

If again in the same way, but with replacement of the 2-amino-4-nitrodiphenylthioether and the 3-chloropropionyl chloride worked as starting materials through suitable amounts of 3-amino-4-nitrodiphenyl ether and chloroacetyl chloride,

609831/1003 ORIGINAL INSPECTED

.254Ü417

3- (2-chloroacetamido) -4-nitrodiphenyläther having a melting point of 109 - 110 obtained ^0C.

(a) A mixture of 28.6 g of phenol, 50 g of 5-chloro-2-nitroaniline, 45.4 g of anhydrous potassium carbonate and 150 ml of dry dimethylformamide was refluxed for 5 hours. The mixture was cooled to room temperature and then treated with 150 ml of water. The precipitated solid was filtered off and ablated from isopropanol rekristalli, wobei.42,9 g of 3-amino-4-nitrodiphenyläther having a melting point of 146 - 148 ⁰ C were obtained.

Example 11

2 3.0 g
A mixture of / 4- (2-benzyloxycarbonylamino-acetamido) -3- (3-methoxycarbonyl-2-thioureido) -diphenylthioäther and a solution of hydrogen bromide in 120 ml of glacial acetic acid (40% w / w.) Was stirred and heated to 4o ⁰ C heated for 30 minutes. The resulting suspension was poured into 400 ml of diethyl ether and the precipitated solid was filtered off and recrystallized from a mixture of methanol and dimethylformamide, l6, lg 4- (2-aminoacetamido) -3- (3-methoxycarbonyl-2-thioureido) -diphenylthioether- hydrobroraid with a melting point of 200-202 ⁰ C (with decomposition) were obtained.

16.1 g of 4- (2-arainoacetamido) -3- (3-methoxycarbonyl-2-thioureido) -diphenyl-thioether hydrobromide were suspended in a mixture of 200 ml of water and 600 ml of chloroform. A solution of 3 * 6 g of sodium carbonate in 80 ml of water was added and the hybrid was stirred vigorously for 20 minutes. The chloroform layer was separated, dried over magnesium sulfate and evaporated. The solid residue was recrystallized from a mixture of methanol and dimethylformamide to give 5.0 g of 4- (2-aminoacetamido) -3- (3-methoxycarbonyl-2-thioureido) -diphenylthioäther having a melting point 168-170 ⁰ C (under Decomposition).

603831/1003

7.0 g of 4- (2-aminoacetajnido) -j5- (3-methoxycarbonyl-2-thioureido) diphenyl thioether were suspended in 150 ml of acetone and 1.8 g of methanesulfonic acid were added with stirring. A clear solution was formed which was then treated with 250 ml of diethyl ether. A gum was formed which slowly solidified as the mixture triturated. The solid was filtered off and recrystallized from ethanol (undissolved material being removed by filtering the hot ethanolic solution). There was thus J5,9 g of 4- (2-aminoacetamido) -3- (j5-methoxycarbonyl-2-thioureido) diphenyl thioether methanesulphonate having a melting point of 181 - I83 ⁰ C (with decomposition).

When working in the same way, but replacing the 4- (2-Benzyloxycarbonylaminoacetamido) -] 5- (3-methoxycarbonyl-2-thioureido) -diphenylthioether as starting material by appropriate amounts of

4- (2-Benzyloxycarbonylaminoacetamido) -3- (3-ethoxycarbonyl-2-thioureido) -diphenyl thioether, 4 - ^ / 2- (N-Benzyloxyc arbonyl-N-methylamino) -acetamido7-3- (3-niethoxycarbonyl-2-thioureido) -diphenyl thioether, j5- (2-Benzyloxycarbonylaminoacetamido) -4- (3-methbxycarbonyl-2-thioureido) -diphenylthioether, . 4- (2-Benzyloxycarbonylaminoacetamido) -5-Ö-methoxycarbonyl-2-thioureido) -4'-methyldiphenylthioether, j5- (2-Benzyloxycarbonylaminoacetamido) -4- (3-methoxycarbonyl-2-thioureido) diphenyl ether and 4 - (2-Benzyloxycarbonylaminoac etamido) -4 '-chloro-3- (3-methoxycarbonyl-2-thioureido) -diphenylthioether were obtained, in some cases without isolation of the hydrobromide salt and in some cases without subsequent preparation of the methanesulfonate salt

4- (2-aminoacetamido) -5- (3-ethoxycarbonyl-2-thioureido) di ■ phenylthioätherhydrobromid, mp I88 -. 190 ⁰ C (. Decomposed) / 4- (2-Aminoace tamido) -j5- ( j5-ethoxycarbonyl-2-thioureido) diphenyl thioether, mp. 168 - 170 ⁰ C (with decomposition), 4- (2-aminoacetamido) -3- (5-ethoxycarbonyl-2-thioureido) -diphenylthioäthermethansulfonat, mp L6J. - 165 ⁰ C (. decomposed), 5- (5-methoxycarbonyl-2-thioureido) -4- / 2- (N-methylamino) -acetamido7-diphenylthioätherhydrobromid, mp 195 -. 196 ⁰ C (under

Decomp.)

60383 1 / 1.0 03

2b4üA17

5- (3-methoxycarbonyl-2-thioureido) -4- _</ 2- (N-methylamino) -acetamido7-diphenylthioäther, mp 175 -. 175 ⁰ C (with decomposition)
3- (2-aminoacetamido) -4- (3-methoxycarbonyl-2-thioureido) -diphenylthioäther, mp l80 -. L82 ⁰ C (with decomposition), 4 _ (2-aminoacetamido) -5- (5-methoxycarbonyl-2. -thioureido) -V-methyldiphenylthioäther, mp 172 -.. 174 ⁰ C (decomposed) 3- (2-aminoacetamido) ~ 4- (3-methoxycarbonyl-2-thioureido) -diphenyläther, mp l80 -. I83 C ⁰ 175 ⁰ C (with decomp.) - (with decomposition), 4- (2-aminoacetamido) -4'-chloro-3- (5-methoxycarbonyl-2-thioureido) -diphenylthioäther, mp 170th.

The starting materials were prepared as follows:

(a) A stirred mixture of 30 g of N-benzyloxycarbonylglycine / prepared according to Ber., 65 ^, 1192, (1932) J and 190 ml of dry diethyl ether was ^{treated at 0 °} C. with 32 g of phosphorus pentachloride for 5 minutes. The mixture was ^{stirred between 0} ° C. and 5 ^° C. for a further 20 minutes and the solution was then filtered and the filtrate was evaporated. The residue was triturated with gasoline (bp 40-βθ ⁰ C) and the gasoline layer decanted off. This treatment was repeated a few times, the temperature being kept below 20 ^° C. A solid was formed which was filtered off and which consisted of 25 g of N-benzyloxycarbonylglycyl chloride, which was used immediately in the next step. 13.0 grams of N-benzyloxycarbonyl glycyl chloride was added all at once to a stirred solution of 10.0 grams of 4-amino-3- (3-methoxycarbonyl-2-thioureido) diphenylthioether (prepared as described in Example 2) in dry dimethylformamide. The temperature of the mixture rose to 35 ^° C. and stirring was continued for 20 minutes. The solution was then poured into water. The resulting oil solidified on rubbing. The solid was filtered off and recrystallized from a mixture of dimethylformamide and methanol, 13.0 g of 4- (2-benzyloxycarbonylaminoacetamido) -3- (3-methoxycarbonyl-2-thioureido) diphenylthioether having a melting point of 184 -. 186 ⁰ C received.

6 0 9831/10 0.3 .- · ■ ■ ■

- 66 - 2543417

When working in the same way, but replacing 4-Amino-j5- (j5-methoxycarbonyl-2-thioureido) -diphenyl thioether as starting material by appropriate amounts of 4-amino-3- (3-ethoxycarbonyl ~ 2-thioureido) -diphenyl thioether, 4- Amino-3- (3-methoxycarbonyl-2-thioureido) -4'-methyldiphenylthioether (prepared according to Example 2), 3-amino-4- (3-methoxycarbonyl-2-thioureido) diphenyl ether (produced according to Example 2) and

4-Amino-4'-chloro-3- (5-methoxycarbonyl-2-thioureido) -diphenylthioether (prepared according to Example 2) were obtained accordingly

4- (2-Benzyloxycarbonylaminoacetamido) -3- (3-ethoxycarbonyl-2-thioureido) -diphenylthioäther, mp l68 -. 170 ⁰ C, 4- (2-Benzyloxycarbonylaminoacetamido) -3- (3-methoxycarbonyl-2-thioureido) - 4'-methyldiphenylthioäther, mp L82 -. I83 ⁰ C (with decomposition)

5- (2-Benzyloxycarbonylaminoacetamido) -4- (5-methoxycarbonyl-2-thioureido) -diphenyläther, mp l64 -. 168 ⁰ C (. Decomposed) and 4- (2-Benzyloxycarbonylaminoacetamido) ^-4-chloro-l J5 (3-methoxycarbonyl-2-thioureido) -diphenylthioäther, mp. 187 I89 ⁰ C (with decomposition).

If one again worked in the same way, but replacing the N-benzyloxycarbonylglycine as starting material with the appropriate amount of N-benzyloxycarbonylsarcosine, 4- _/ / 2- (N-benzyloxycarbonyl-N-methylamino) -acetamido7-j5- (3- methoxycarbonyl-2-thioureido) -diphenylthioäther having a melting point 178-180 ⁰ C (with decomposition).

A mixture of 12.6 g dry potassium thiocyanate, 130 ml Acetonitrile and 12.3 g of methyl chloroformate stirred at room temperature for 90 minutes. 17.8 g of 4-amino-3- (2-benzyloxycarbonylaminoacetamido) diphenylthioether were then added portionwise to the stirred suspension. After stirring for an additional 90 minutes, became the mixture is poured into 1500 ml of water and the resulting solid filtered off and from a mixture of methanol

$ 09831/1003

dimethylformamide and recrystallized to give (2-Benzylo ^ rcarbonylaminoacetamido) -4- (3-methoxycarbony1-2-thioureido) -diphenylthioäther 14.4 g of 5- having a melting point of 175 - received 176 ⁰ C (with decomposition).

(b) 4-Amino-3- (5-äthoxyc arbony1-2-thi oureido) -diphenylthioäther (mp. 168 - 170 ⁰ C with decomposition) was prepared according to Working Example 2 to give but as a starting material by the Methoxyearbonylisothiocyanat suitable amount Äthoxycarbonylisothiocyanat replaced, via the intermediate 3- (3-ethoxycarbonyl-2-thioureido) -4-nitrodiphenylthioäther (mp. 110 - 112 ⁰ C).

4-Amino-3- (2-benzyloxycarbonylaminoacetamido) -diphenylthioether was prepared as follows:

40.0 g of N-benzyloxycarbonylglycyl chloride (freshly prepared as described above) were dissolved in 50 ml of dry dimethylformamide and the solution was added to a solution of 24.6 g of 3-amino-4-nitrodiphenylthioether (prepared according to Example 1) in 250 ml of dry dimethylformamide given. The mixture was stirred for 1 hour at below 35 ^° C. and was then poured into 1 l of water. The resulting oil solidified upon rubbing. The solid was filtered off and recrystallized from ethanol, whereby 27.7 g of 3- (2-Benzyloxycarbonylaminoacetamido) -4-nitrodiphenylthioäther having a melting point 117-120 ⁰ C were obtained.

A stirred mixture of 23.3 g of 3- (2-Benzyloxyearbonylaminoacetamidd) -4-nitrodiphenylthioether, 3.72 g of ferrochloride tetrahydrate, 290 ml of methanol and 64 ml of water were refluxed and mixed with 18.7 g of reduced iron powder treated for 5 minutes. The mixture was refluxed for 1 hour and then filtered while warm. The filtrate was diluted with δΟΟ ml of water and the resulting The solid is filtered off and recrystallized from ethanol, 15.4 g of 4-amino-3- (2-benzyloxycarbonylamino-

609831/1003

acetamido) -diphenylthioäther having a melting point of 134 - 136 ⁰ C received.

Example 12

suspension
A stirred / of 5 * 6 g of 2-amino-1- (3-methoxycarbonyl-

2-thioureido) -4-thiocyanatobenzene in 19O ml dichloromethane

were all at once at room temperature with 3. »82 g of N, N-dimethyl ~

hydrochloride

glycylchlorld treats. Stirring was continued for 1 hour and the mixture was allowed to stand overnight. The solid was filtered and recrystallized from methanol to obtain 4.35 g of l- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) -4 ~ thiocyanatobenzene hydrochloride with a melting point 192-193 ⁰ C ( with decomposition).

The starting material 2-amino-1- (3-methoxycarbonyl-2-thioureido) -4-thiocyanatobenzene was made as follows:

By working as in Example 6, but replacing the 3-amino-4'-chloro-4-nitrodiphenylthioether as starting material with the appropriate amount of 2-nitro-4-thiocyanatoaniline (prepared as described in Example 6), 1- (3 -methoxycarbonyl-2-thioureido -2-nitro-4-thiocyanatobenzene) with a Schmel ^ oint of 171 - 172 obtained ^0C.

A stirred mixture of 27.0 g of 1- (3-methoxycarbonyl-2-thioureido) -2-nitro-4-thiocyanatobenzene, 5.85 g of ferrochloride tetrahydrate, 450 ml of methanol and 100 ml of water was refluxed with 29.7 g of reduced Treated iron powder in portions for 5 minutes. The mixture was heated under reflux for 1 hour, 250 ml of methanol was added and the boiling solution was filtered off hot. The piltrate was evaporated to dryness and the residue extracted with 3 × 500 ml of boiling methanol. The extract was evaporated and the residue: recrystallized from methyl ethyl ketone (removing the undissolved material by filtering the hot solution), 6.5 g of 2-amino-1- (3-methoxycarbonyl-2-thioureido) -4-thiocyanatobenzene with a melting point of 174 - 176 ⁰ C (below

609831/1003

-69- 2 b 4 9 A 1 7

Decomposition).

Example 13

A solution of 1.0 g of 4- (2-chloroacetamido) -3- (3-ynethoxycarbonyl-2-thioureido) -diphenylthioether in 20 ml of dry toluene was treated with a solution of dimethylamine in ethanol (0.9 ml; 33 % W / W) and the mixture was stirred for 1 hour and then left to stand at room temperature for 3 days. The solution was washed with 2 × 20 ml of water and then dried over magnesium sulfate and evaporated. The remaining solid was recrystallized from ethanol (with removal of any undissolved material by filtering the hot solution), 0.2 g of 3- (3-methoxycarbonyl-2-thioureido) -4- (2-dimethylaminoacetamido) diphenylthioether having a melting point from 148 - 1 ^ 9 ⁰ C (with decomposition) received.

The 4- (2-chloroacetamido) -3- (3-methoxycarbonyl-2-thioureido) -diphenylthioether, which was used as the starting material was prepared as follows:

A mixture of 3 * 33 g of 4-amino-3- (3-niethoxycarbonyl-2-thioureido) diphenylthioether (prepared as described in Example 2), 40 ml of dry toluene and 1.24 g of chloroacetyl chloride was refluxed for 75 minutes . The mixture was then filtered hot and the filtrate cooled to room temperature. The resulting solid was filtered to yield 3 * 15 g of 4- (2-chloroacetamido) -3- (3-methoxycarbonyl-2-thioureido) -diphenylthioäther having a melting point of 145 - 147 ⁰ C were obtained (with decomposition).

6 09831/1003

2549A17 ^

Example 14

A mixture of 2.97 g of 4-amino-5- (5-methoxycarbonyl-2-thioureido) -dipheny1-thioether (prepared as described above in Example 2), 1.4o g !!, N-dimethylglycine hydrochloride and 50 ml Dichloromethane was added dropwise with 1.5 g of phosphorus oxychloride treated. The mixture was then stirred and refluxed for 8 hours, then allowed to cool. 50 ml of water were added added with stirring and the mixture was filtered. The resulting solid was in a mixture of 100 ml Suspended water and 100 ml of chloroform, and the mixture was treated with saturated sodium bicarbonate solution with stirring, until a pH of 8 was reached. The chloroform layer was separated, dried over magnesium sulfate and evaporated and gave a remaining solid which was recrystallized from isopropanol and 1.5 g of 3- (j5-methoxycarbonyl-2-thioureido) -4- (2-dimethylaminoacetamido) -dipheny 1-thioether of F «147-148 ° C (decomp.) Resulted.

Example 15 -

A solution of 2.0 g of 4- (j5-methoxycarbonyl-2-thioureido) -j5- • (2-dimethylaminoacetamido) -dipheny 1-thioether (prepared as described above in Example 1) in 100 ml of acetone was mixed with Treated 0.71 g of methyl iodide. The flask was sealed and left for 4 days. Then there was excess diethyl ether added and the solvent from the gummy mass, which separated, decanted. The gummy mass was treated with a further amount of 80 ml of diethyl ether and gave a solid which was recrystallized from ethanol and 0.7 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-trimethylammonioacetylamino) -diphenyl-thioether iodide of m.p. 162-164 ° C (dec.).

Example 16

A mixture of 10.3 g of dry potassium thiocyanate and 75 ml of ethyl acetate was heated to 60 ° C. with stirring and with 14.6 g

809831/1003. . ■ ■

-71- 254P.417

Isobutyl chloroformate treated dropwise over 5 minutes. The mixture was stirred at 60 ° C. for 2 hours and then cooled and filtered. The filtrate became a solution of 10.0 g of 4-amino-3- (2-dimethylaminoacetamido) diphenyl all at once -thioether (prepared as described above in Example 1) given in 100 ml of glacial acetic acid at room temperature. The mixture was stirred for 4 hours and then left to stand overnight. The reaction mixture was poured into 300 ml of water and by treatment with aqueous 50 # (w / v) sodium hydroxide solution neutralized. The solution was extracted with 2 × 100 ml of ethyl acetate and the extract was dried over magnesium sulfate and evaporated. The resulting oil was dissolved in 200 ml of diethyl ether and with an excess of a solution of Treated hydrogen chloride in diethyl ether. The solid formed was recrystallized from isopropanol and then in 250 ml Suspended in water. The suspension was made alkaline by adding excess sodium carbonate and then with chloroform extracted. Evaporation of the chloroform extract gave 3 * 1 g of 3- (2-dimethylaminoacetamido) -4- [3- (2-methylpropoxyearbonyl) -2-thioureido] diphenyl thioether from P = 104 - 107 ° C.

If you work in a similar way, but as a starting material used isobutyl chloroformate replaced by a corresponding amount of n-butyl chloroformate, see above became 4- (3-n-butoxycarbonyl-2-thioureido) -3- (2-dimethylamineacetamido) -diphenyl-thioether from P = 115 - 116 ° C (decomp.).

Example 17

If one works in a similar manner as described above in Example 10, but the pyrro- used as starting material. lidine was replaced by a corresponding amount of morpholine, so was 4- (3-methoxycarbonyl-2-thioureido) -3- (2-morpholinoacetamido) diphenyl thioether from P = 183 ° C (decomp.) via the following intermediates

3- (2-Morpholinoacetamido) -4-nitrodiphenyl thioether, from P = 169 - 171 ° C and ■

G09831 / 1003

25 4 3 417

4 ~ amino-J5 (2-morpholinoacetamido) diphenyl thioether P = ^128-0

Example 18

If one works in a similar manner as described above in Example 10, but the pyrrolidine used as starting material is replaced by an appropriate amount of di-n-propylamine, 4- (5-methoxycarbonyl-2-thioureido) -3- (2-di -n-propylaminoacetamido) -diphenyl-thioether with a melting point of 133 - 135 ° C (decomp.) produced via the intermediates

4- Nitro-3- (2-di-n-propylaminoacetamido) diphenyl thioether (isolated as the hydrochloride salt, P = 125 - 126 ° C) and

4 - amino-3- (2-di-n-propylaminoacetamido) diphenyl thioether (isolated as the dihydrochloride salt, m.p. = 185-187 ⁰ C).

Example 19

If you work in the same way as described above in Example 10, but the compounds ² I-AmInO-J- (2-dimethylaminoacetamido) diphenyl thioether and methyl chloroformate used as starting materials by corresponding amounts of 2- (2-dimethylaminoacetamido) -4-methylsulfonylaniline or ethyl chloroformate V / so vmrde 2- (j5 ~ A "thoxycarbonyl-2-thiOrureido) -1- (2-dimethylarainoacetamido) -4-methylsulfonylbenzene (isolated as the hydrochloride salt, F = 196-198 ⁰ C) produced.

The 2- (2-dimethylaminoacetamido) -4-methylsulfonylaniline used as the starting material was made as follows:

(a) If one worked as described above in Example 10 (a), but the 4-nitro-j5- (2-pyrrolidin-1-ylacetamido) -diphenyl-thioether used as starting material with an appropriate amount of 2- (2-dimethylaminoacetamido ) -4-methylsulfonyl-1-nitrobenzene replaced, as 2- (2-dimethylaminoacetamido) -4-methylsulfonylaniline from F = 130 was - 132 ⁰ C.

609831/1003

L O H- JHI /

(b) If you worked in a similar manner as described above in Example 10 (b) (i), but the compounds used as starting materials 5- (2-chloroacetamido) -4-nitrodiphenyl thioether and pyrrolidine by corresponding amounts of 2- (2-bromoacetamido) -4-methylsulfonyl-l-nitrobenzene and dimethylamine replaced, it was 2- (2-dimethylaminoacetamido) -4-methylsulfonyl-l-nitrobenzene of P = 166 - 168 ° C prepared.

(e) If one worked as in Example 10 (c) above, but the compounds 3-Amino-4-nitrodiphenyl-thioether used as starting materials and 3-chloropropionyl chloride by corresponding Replaced quantities of 4-methylsulfonyl-2-nitroaniline and bromoacetyl bromide, thus became 2- (2-bromoacetamido) -4-methylsulfonyl-1-nitrobenzene from P = 155 - 158 ° C (decomp.).

(d) 73 g of 2-chloro-4-methylsulfonyl-l-nitrobenzene (prepared according to the method described in French Patent 1,509,499), 4θΟ ml of ethanol and 44 g of ammonia 8 hours were combined in a pressure vessel at 120 ⁰ C heated. The kettle was then cooled and opened and the solid filtered off and recrystallized from ethanol to give 19 * 0 g of 4-methylsulfonyl-2-nitroaniline by F = 195-198 ⁰ C.

Example 20

If you worked in a similar manner as described above in Example 2, but the 4-amino-3- (3-methoxycarbonyl-2-thioureido) diphenyl thioether used as starting material by the corresponding amount of 2-amino-4- [2- (Ethylthio) ethoxy] -1- (3-methoxycarbonyl-2-thioureido) benzene and then worked in a manner similar to that described above in Example 7, 4 - [? - (Ethylthio) ethoxy] -1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene from P = 112 - 113 ⁰ manufactured C (dec.).

The 2-amino-4- [2- (ethylthio) ethoxy] -1- (3-methoxycarbonyl-2-thioureido) benzene used as starting material was made as follows:

609831/1003

The procedure was similar to that described above under Example 2, but the 3 ~ (3-methoxycarbonyl-2-thioureido) -4-nitrodiphenyl thioether used as starting material was replaced by a suitable amount of 4- [2- (ethylthio) ethoxy] -l- (3-methoxycarbonyl-2-thioureido) -2-nitrobenzene replaced, 2-amino-4- [2- (ethylthio) ethoxy] -1- (3-methoxycarbonyl-2-thioureido) benzene from P. = 135-136 ⁰ C was prepared.

If one is carried out in a manner similar to that described above in Example 6 (b) works, but the 3-amino-4'-chloro-4-nitrodiphenyl thioether used as starting material replaced by an appropriate amount of 4- [2- (ethylthio) ethoxy] -2-nitroaniline, so was 4- [2 -. (Ethylthio) ethoxy] -1- (3-methoxy carbonyl-2-thioureido) -2-nitrobenzene from F = 115 - 117 ° C produced.

A solution of 17.5 g of 4-amino-3-nitrophenol in 300 ml of ethanol was treated with 6.38 g of solid potassium hydroxide. The mixture was with a solution of 21.2 g of 2-bromoethyl-ethyl-thioether in Treated 100 ml of ethanol and stirred for 4 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 200 ml of chloroform. The chloroform solution was with 200 ml of aqueous 10 $ -iger (ow. / vol), sodium bicarbonate solution washed, dried over magnesium sulfate and evaporated to give 23 * 4 g of 4- [2- (ethylthio) ethoxy] -2-nitroaniline in the form of a dark red oil which was used in the next step without further purification.

The compounds of general formula I are useful as anthelmintic agents in the form of compositions in dosage units administered, and the present invention also relates to the therapeutically useful, particularly veterinary compositions, which as the active ingredient at least one of the benzene derivatives of the formula I together with an amount of one or more compatible and pharmaceutically acceptable carriers or excipients. The invention particularly relates to Compositions for oral administration, e.g. as tablets, pills, capsules or spheres, or in particular as a paste, gel or potion.

609831/1003

Solid compositions for oral administration include tablets, Pills, balls or granules, which optionally with may be coated with a pharmaceutically acceptable alkali-stable or acid-stable material (e.g. an intestinal coating), and dispersible powder. With such solid compositions is the active ingredient or ingredients with at least one inert diluent, such as potato starch, alginic acid, sugar, Lactose or a resin mixed together. The compositions can also, as is customary, in addition to the inert diluents still contain additives, e.g. lubricants such as magnesium stearate. Semi-solid compositions for oral administration. include pastes and gels containing the active ingredient and a suitable inert diluent such as polyethylene glycol (6000). Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, Syrups and elixirs containing the inert diluents customary in this field, such as water or liquid Paraffin. In addition to the inert diluents, such compositions can also contain compatible auxiliaries, such as wetting agents, Suspending agents and emulsifying agents and stabilizing agents, thickening agents, fragrances, sweeteners or flavorings contain. The compositions according to the invention for oral Administration also include capsules of absorbable material, such as gelatin, which contain one or more active ingredients with or without Addition of diluents or excipients included.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic or organic Solutions, suspensions and emulsions. Examples of organic solvents or suspending agents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also use auxiliaries such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants, contain. They can be sterilized, for example by filtering through a bacteriological filter, by incorporation of sterilizing agents in the compositions or by

609831/1003

Heat. They can also be in the form of sterile solid compositions prepared in sterile water or other suitable sterile injectable medium immediately be solved before use.

The percentage of the benzene derivatives of the formula I in the above compositions can vary, it is only necessary that such a proportion be present that a suitable dosage is achieved to achieve the desired therapeutic effect. In general, the compositions comprising from about 5 wt .- $ to about 90 wt -. Contain% active ingredient, satisfactory.

The compounds of the general formula I according to the invention can expediently also be administered as anthelmintics by dermal application and absorption through the skin of the animal, and the present invention also includes liquid therapeutically useful compositions, in particular for veterinary medicine, which are suitable for dermal administration and which are used as active ingredients at least one benzene derivative of formula I together with a substantial amount of a liquid pharmaceutically acceptable carrier suitable for dermal application. Compositions for dermal administration according to the invention preferably contain a solution of at least one benzene derivative of the general formula I in a liquid pharmaceutically acceptable solvent, for example a hydrocarbon, for example xylene, toluene, benzene or a mixture of aromatic hydrocarbons whose boiling point is between 130 and 250 ^° C is, for example between 180 and 220 ⁰ C, or paraffins with 6 to 20 carbon atoms, halogenated hydrocarbons, such as carbon tetrachloride, ketones, such as cyclohexanone or butanone, esters, such as ethyl acetate, ethyl benzoate or glyceryl triacetate, ethers, such as diisopropyl ether or tetrahydrofuran , Alcohols, e.g. alkanols with 2 to 8 carbon atoms (e.g. butanol, isopropanol or amyl alcohol) or glycols (e.g. propylene glycol), amides, e.g. lower alkyl amides (e.g. dimethylformamide), suI-

fonen, ζ .B .J JHa lky lsulfonen (e.g. Dime thy Is ulfon) or sulfolane in low-1

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254Ü417

or sulfoxides, for example lower dialkyl sulfoxides (for example dimethyl sulfoxide) or mixtures of such solvents. Preferred carriers for compositions which are suitable for dermal application are amyl alcohol and dimethyl sulfoxide and mixtures thereof. Liquid compositions which are suitable for dermal application preferably contain a thickening agent, so that the flow of the liquid composition from the skin of the animal is reduced and thus the absorption of the active ingredient through the skin of the animal is facilitated. Suitable thickeners are, for example, soaps, fats and waxes, for example lanolin, mineral or vegetable oils and polymers, for example polyisobutylene. Liquid compositions which are suitable for dermal application can also contain systemic insecticides which are known to be suitable for dermal administration to animals, for example phosalone and bitteraloe, which prevent other animals from licking the treated areas of skin. The liquid compositions for dermal administration can be applied to the skin of the animal by conventional techniques, for example by dipping, spraying and pouring over the back of the animal. The percentage of benzene derivative of the formula I in the liquid compositions suitable for dermal application can vary; it is only necessary that it is such an amount that a suitable dosage is used to achieve the desired therapeutic effect. Preferably, the liquid compositions suitable for dermal administration contain from 1 % to 10 % w / v. of benzene derivative of the formula I, from ^ 5 to 95 % v / v. on liquid pharmaceutically acceptable carrier and from 5 % to 50 % w / v. of thickener and / or systemic insecticide.

For therapeutic purposes, especially when continuous administration over a longer period of time is desired, can the compounds of general formula I dissolved or dispersed or mixed with the feed, the drinking water and others fluids normally consumed by the animals or in compositions containing the benzene derivatives with any other suitable inert, physiological

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innocuous carrier or diluent which can be administered orally, dispersed or admixed therewith. By the term "inert physiologically harmless carrier or diluent" is meant a carrier or diluent meant that essentially does not react with the active ingredient and is not harmful to the animals when administered orally is. Such compositions can be in the form of powders, flakes, food items, licks, solutions, suspensions and Emulsions are administered to the animals in order to apply the desired dosage of the bensol derivative, or they can be used as Concentrates or supplements that are normally used with additional carriers, feed, drinking water or others Liquids consumed in animals are diluted. Suitable inert, physiologically harmless carriers or Diluents include cereals or grains, e.g. wheat flour or meal, corn gluten, lactose, glucose, sugar, Molasses, talc, kaolin, calcium phosphate, potassium sulfate, sodium chloride, Urea and diatomaceous earth such as kieselguhr. Concentrates or supplements which can be incorporated into the Drinking water or other liquids normally consumed by the animal to obtain solutions, emulsions or stable ones Suspensions are provided, the active ingredient can also be used together with surfactants, dispersants or surfactants Contain emulsifiers, for example Teepol, polyoxyethylene (20) sorbitan monooleate or the condensation product of ß-naphthalinesulfonic acid with formaldehyde, with or without a physiologically harmless, preferably water-soluble carrier or Diluents, for example sugar, glucose, or an inorganic salt such as potassium sulfate; or concentrates or supplements in the form of stable dispersions or solutions, which can be obtained by mixing the aforementioned concentrates or supplements with water or another suitable, physiologically harmless, inert liquid carrier or diluent or mixtures thereof.

The compositions described above can be prepared by benzene derivatives of the formula I with the inert, physiologically harmless carriers or diluents in any

ΦίΘ-983 1- / 1003

mixed in a manner known in the art. Solid compositions are conveniently prepared by using the benzene derivatives with the feed or other solid carriers or diluents uniformly and thoroughly intimately mixed or dispersed by methods such as grinding, stirring, grinding or centrifuging or by dissolving the benzene derivatives in a solvent such as water or a suitable organic solvent, dispersing the solution thus obtained in

leinera /

the feed or the use of solid carriers or diluents and removing the solvent in any suitable known manner. Medicated feed can also be made by using concentrates or supplements, which contain higher levels of active ingredient so that feed results in which the benzene derivatives are uniformly distributed in the desired concentration are. The desired concentration of active ingredient in the compositions according to the invention is achieved by that a suitable proportion of the benzene derivatives to the carrier or diluent is selected.

The medicated feed normally contains between 0.001 wt .- ^ and J5 wt .- ^ of benzene derivatives of the formula I in order to give the required dosage. Concentrates and additives normally contain between 0.02 and 90% by weight 3, preferably between 0.1 and 50% by weight, of benzene derivatives and, if desired, are suitably diluted as described above, so that the required dosage results.

The feed, drinking water and other liquids normally consumed by animals and prepared with the active ingredient Compositions containing the benzene derivatives according to the invention of the formula I dispersed or mixed with another suitable inert carriers or diluents, as described above, including concentrates or additives or Supplements form a further subject of the invention.

The anthelmintic compositions according to the invention can

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Marg

also contain bacteriostats, bactericidal agents, sporicidal agents, and pharmaceutically acceptable coloring agents. If desired, the compositions can also contain therapeutic auxiliaries, for example agents against flukes or liver fluke, such as, for example, 4-cyano-2-iodo-6-nitrophenol, hexachloroethane, carbon tetrachloride, 3,3 ', 5 * 5' , &, & -hexachlor- 2,2'-dihydroxydiphenylmethane, 2,2'-dihydroxy-3,3 ', 5,5', 6-pentachlorodiphenylmethane, 2,2 '-dihydroxy-3,3', 5,5 ', β-pentachlorobenzanilide, 2 , 2'-dihydroxy-3,3 ^! -dinitro-5,5'-dichlorodiphenyl, bis [2- (4-acetamidophenoxy) -ethyl] -ether or 2-acetoxy-4'-chloro-JiS-diiodobenzanilide, 2- (4-thiazolyl) -benzimidazole, 5 ( 6) Isopropoxycarbonylamino-2- (4-thiazolyl) -benzimidazole, methyl 5- (6) -butyl-2-benzimidazole-carbamate, methyl-5 (6) -benzoyl-2-benzimidazole-carbamate, 6-phenyl-2,3,5 , 6-tetrahydroimidazo [2, lb] thiazole, trans-1,4,5,6-tetrahydro-1-methyl-2 ^ - (2-thien-2 '-ylvinyl) -pyrimidine, phenothiazines cyanoacethydrazide, piperazine and its salts such as piperazine adipate, l-diethylenearbamoyl-4-methylpiperazine, tetrachlorethylene,

4,4'-dichloro

2,2'-dihydroxydiphenylmethane, N- (2-chloro-4-nitrophenyl) -5-chlorosalicylamide, N, N-dibutyl-4-hexyloxynaphthamidine, trans-1,4-bis (2-isothiocyanatoethyl) cyclohexane and 1-styrylpyridinium salts, e.g. bromide, embonate, amsonate or isethionate.

The new compounds of formula I can be used as fungicides against fungi which affect the growth of plants, seeds and fruits have a pathogenic effect, can be used in the form of fungicidal compositions suitable for use in agriculture and as active ingredient at least one benzene derivative of the general formula I together with one or more diluents, which are compatible with the benzene derivatives and suitable for use as fungicidal compositions. The compositions preferably contain between 0.005 wt. and 95 wt .- ^ of the compounds of general formula I. Suitable solid diluents include aluminum silicate, kieselguhr, tricalcium phosphate, cork powder, adsorbent carbon black, Magnesium silicate, clay such as kaolin, bentonite or attapulgite, or a compatible solid wetting, dispersing or emulsifying agent. The compositions containing the solid diluents

9831/1003

.81-2bVJ4i7

Settlements, which are in the form of granules or wettable powders are prepared by impregnating the solid diluents with solutions of the compounds of the general Formula I in volatile solvents and evaporating the solvents or by injecting such compounds of the general formula I, which are viscous liquids at room temperature, under high pressure in a suitable powder mixer, which contains the solid diluent or diluents and optionally comminuting the product, so that powders are obtained. The wetting, dispersing and emulsifying agents which may be present are in particular wettable Powders, which can be of the ionic or non-ionic type, for example sulforicinoleates, quaternary ammonium derivatives or products based on condensates of thyene oxide with nonyl and octy! phenol, or fatty acid esters of anhydrosorbitols, which were made soluble by etherification of the free hydroxyl groups by condensation with ethylene oxide, or Mixtures of these types of agents. Wettable powders according to the invention can be treated with water immediately before use so that ready-to-use suspensions result.

Liquid compositions can be in the form of solutions, suspensions, Slurries and emulsions of the compounds of the general Formula I ,, which, if desired, wetting, dispersing

v go rl ie gen.) or emulsifiers are incorporated könnenTYDiese emulsions, suspensions and solutions may be prepared using aqueous, organic or aqueous-organic diluents, for example acetophenone, isophorone, toluene, xylene and mineral, animal or vegetable oils (and mixtures these diluents), which may contain wetting agents, dispersants or emulsifiers of the ionic or nonionic type or mixtures thereof, for example those of the types described above. If desired, the emulsions containing the compounds of the general formula I can be used in the form of self-emulsifying concentrates, which the active ingredients dissolved in emulsifiers or in solvents which contain emulsifiers which with the active

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■ 254Ü417

Compatible with the substance, and by simply adding water to such concentrates the ready-to-use Compositions are obtained. Fungicidal compositions in the form of aerosols containing the compounds of the general Formula I included are also within the scope of the invention. If desired, the fungicidal compositions can according to the invention also contain other auxiliaries, such as adhesives.

The compositions according to the invention to be used in agriculture can also both the compounds of formula I and pesticides, such as insecticides, for example / = • 1 * 2,3,4,5, β-hexachlorocyclohexane, or other fungicides, for example 3a, 4,7i7a-Tetrahydro-N- (trichloromethanesulfonyl) -phthalimide contain.

As a result, one method of destroying fungi which are pathogenic to plants is to use the fungicidal ones Compositions which the compounds of formula I if necessary after suitable dilution, include, on agricultural areas which are infested with these fungi are. The expression "agriculturally cultivated areas" means areas whereupon economically valuable harvests grow. Preferably the fungicidal compositions are used in amounts from 0.25 to 3 lbs. Benzene derivative per acre (0.280-3.3501Sg per ha applied, in particular in the form of aqueous sprays, which are produced by diluting concentrates with water.

A method for protecting seeds against fungi is also provided, which consists in treating the seeds with fungicidal compositions which contain the compounds of the formula I, optionally after dilution. The fungicidal compositions are preferably applied to the seeds or the seeds in amounts of 0.05 % to 0.2 % benzene derivative, in particular in the form of dry powder or as a slurry.

A method for protecting fruits after the

1/10

2b4ü417

Harvest against fungi created, which consists in the fact that the Fruits with the fungicidal compositions which contain the compounds of formula I, optionally after dilution, be treated. Preferably the fungicidal compositions are applied to the fruit in amounts from 0.25 to 3.0 lbs. Benzene derivative per 100 gallons of water (0.025 - 0.300 kg per hl) applied, especially in the form of a solution in which the fruits are dipped.

The new compounds of general formula I can be used as fungicides applied against fungi pathogenic against animals in the form of therapeutically useful compositions, said compositions having at least one of the compounds together with a pharmaceutically acceptable carrier or coating of the type as described above as suitable for the use of compounds of the general formula I as anthelmintics was to include. Therapeutically useful compositions containing at least one of the new compounds of the general Formula I contain, for use against fungi which are pathogenic against animals, formulations for the topical application are suitable, e.g. lotions, ointments and creams.

The following examples are intended to guide the formulation of therapeutically useful and fungicidal compositions containing the Benzene derivatives of the formula I contain, explain in more detail.

It should be mentioned that in each of the following examples, unless otherwise specified, every other compound of the formula I can be used instead of those specifically mentioned, it being important to note that the proportions of the constituents and methods of making the compositions can be modified depending on the physicochemical properties of the compound of formula I used, such modifications being used to formulate therapeutically useful or fungicidal Compositions can be determined by a simple preliminary experiment.

609831/1003

Example 21

Tablets of the following formulation:
4 ~ (3_Methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenylthioether 250 mg lactose 200 mg

Strength 50 mg

Polyoxyethylene sorbitan monolaurate 0.5 mg

Magnesium stearate 5 mg

were made by mixing the benzene derivative and the lactose with part of the starch and using a $ 5 starch adhesive solution, which contained the polyoxyethylene sorbitan monolaurate, granulated. The mixture was passed through a 20 mesh British Standard sieve (mesh size approx. 0.776 rom), sieved, dried and the remainder of the starch was taken along with the magnesium stearate incorporated into the mixture. After a second sieving through a 20 mesh British Standard sieve (lidite mesh size about 0.776mm) the mixture was compressed into tablets.

Example 22

A wettable powder was made from the following ingredients

manufactured: *

4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether $ 75 w / w

Diatomaceous earth 15 $ ""

Micronized. Silica ^ .._, _, _, 2 $ ""

Wetting agent CKxung of polyoxyethylene alkyl ethers and polyoxyethylene fatty acids

their esters) 8 $ ""

The components were mixed and ground in a jet mill. '

Example 23

It became a wettable powder from the following components

manufactured:

4- (3-methoxycarbonyl-2-thioureido) -3- (2-

dimethylaminoacetamido) diphenyl thioether 52 $ wt / wt

finely divided synthetic magnesium silicate 39 $ ""

micronized silica - $ 2

Hetting agent (mixture of polyoxyethylene alkyl ethers, polyoxyethylene fatty acids and their esters) 7 $ ""

€ 09831/1003 -

The components are mixed and ground in a jet mill.

Example 24

1 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoaceta ~ mido) -diphenyl-thioether, which was previously sieved through a 40 mesh British Standard sieve (mesh size approx. 0.457 mm), was packed in a gelatin capsule.

Example 25

A preparation for oral administration was obtained by adding 1 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl thioether, which had previously been passed through a 40 mesh British Standard sieve (mesh size about 0.457 mm) was sieved, and 10 g of polyethylene glycol 6000 was ^{mixed at 50 0} C and ^{cooled to 25 0} C, so that a gel was obtained.

Example 26

18 parts (w / w) 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl-thioether were added to 82 parts (w / w) of wheat fodder meal and mixed intimately so that a concentrate resulted which could be incorporated into animal feed, in an amount necessary to achieve an anthelmintic effect of the benzene derivative in the animal feed consumed by the eggs.

Example 27

5 parts by weight of 4 (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether were added to 20 parts (w / w) limestone powder. The mixture was milled and yielded a concentrate suitable for incorporation into animal putter in an amount sufficient to produce a anthelmithically effective amount of the benzene derivative in the from SPier to give up consumed putter.

Example 28

An oral suspension for use as an anthelmintic was obtained by mixing 4.4 g

609831/1003

Diethyl carbamazine citrate (prepared as described in U.S. Patent 2,467,895) and 19.6 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether "in the form of a $ 52 [w / w] wettable powder as described in Example 23, with 140 ml of water.

Example 29

An oral suspension for use as an anthelmintic was obtained by mixing 10 g

1-styrylpyridinium amsonate monohydrate (prepared as in the British Patent 1,221,061), which was previously sieved through a 60 mesh British Standard sieve (clear mesh size about 0.251 ran) and 19.6 g of 4- (3-methoxycarbonyl ~ 2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether in the form of a 52% (w / w / w / w) wettable powder, prepared as described in Example 23,

with 140 ml of water.

Example 30

A solution for oral administration as an anthelmintic was obtained by adding 10 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether methanesulfonate and 10 g of 1-styrylpyridinium isethionate were dissolved in 100 ml of water. This solution was sterilized by filtering through a bacteria-retaining filter to give a sterile composition, which is suitable for parenteral administration as an anthelmintic.

Example 31

A solution for oral administration as an anthelmintic was obtained by adding 4.4 g of diethyl carbamazine citrate and 10 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether methanesulfonate were dissolved in 100 ml of water. This solution was made by filtering it through a bacteria retentive filter sterilized and yielded a sterile composition suitable for parenteral administration as Anthelmintic: is appropriate.

609831 / 1ÜÖ3

Example 32

A wettable powder was obtained by mixing:

4- (3-methoxycarbonyl-2-thioureido) -3- (2-aimethylaminoacetamido) -diphenyl-thioether-

hydrochloride 50 parts w / w

Texofor PX 500 (an alky.lphenol-polyoxy-

ethylene condensate) 10 »» »

Celite 281 (a finely divided diatomaceous earth) 40 " ⁿ "

in a ribbon mixer.

Example 33

A wettable powder was obtained by mixing: 4- (3-M _e thoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl-

thioether hydrochloride 50 parts w / w

Belloid TD (a polymethyl-bis-naphthyl-

sodium sulfonate) 10 "" "

Clarcelflo SAS (a perlite with a large surface) 35 "" "Aerosil (a finely divided silicon dioxide) 5" "" in a ribbon mixer.

Example 34

A liquid concentrate in suspension was obtained

by mixing:

4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl-thioether-

hydrochloride 60 parts w / w

Bentonite 3 "" "

Cutafor 09 (a polyethoxylated alkylamine) 10 "" "

White Spirit (a petroleum distillate) 10 "» "

Example 35

10 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl-thioether were dissolved in 100 ml of dimethyl sulfoxide and resulted in a solution which is suitable for dermal or parenteral administration.

60983 1/1003

Example 56

A mineral lick was made in the usual way from

4_ (3_Methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl-thioether 2 parts w / w

Sodium chloride 195 "" "

other minerals (e.g. magnesium compounds 3 "" " and phosphorus compounds) and vitamins, which are desirable when feeding animals.

Example 37

A liquid feed additive was made from 4- (3-methoxycarbonyl-2-thioureido) -3- (2-

dimethylaminoacetamido) diphenyl thioether 1 part w / w

Molasses 650 pieces "»

Water 349 »» »

Example 38

Drinking water was treated so that it was used for continued medication was suitable for animals by adding 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl-thioether hydrochloride (0.01% w / w) were dissolved.

Example 39

A solution for oral administration as an anthelmintic was obtained by adding 10 g of 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether methanesulfonate were dissolved in 100 ml of water.

This solution was obtained by filtering through a bacterial barrier Filter sterilized and gave a sterile composition suitable for parenteral administration as an anthelmintic suitable is.

Example 40

250 parts (w / w) 4- (3-methoxycarbonyl-2-thioureido) -3- (2-dimethylaminoacetamido) -diphenyl-thioether were with 6 parts (w / w) Atlox 4855 and 1 part (w / w) Aerosil 200 and water

609831/1003

2549A Ί 7

made up to 500 parts (w / w) and the mixture was run through a colloid mill, so that a slurry revealed those for use as seed "or seed" treatment agents was suitable.

Atlox 4855 is a polyoxyethylene triglyceride / alkylarylsulphonate mixture and Aerosil 200 is a microfine silica.

Example 41

0.4 lh = 181.4 g of 4- (3-methoxycarhonyl-2-thioureido) -3- (2-dimethylaminoacetamido) diphenyl thioether hydrochloride were dissolved in 100 gallons = 454.6 liters of water to produce a solution which was "used as a dipping agent for fruit." suitable after harvest.

609831/1003

Claims (1)

Claims v / orin R is a straight or branched chain alkyl group with not more than 4 carbon atoms "means, R is a group of the formula -SR ⁵ , -SOR ³ , -SO ₂ R ³ , -OR ³ , -SCOIiH ₂ , -SCIf or -Ϊ (CH ₂ ^ T ¹ R ⁴ , [ R ^ denotes a straight or branched chain alkyl group with not more than 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a straight or branched chain alkenyl or alkynyl group with 3 to 6 carbon atoms, an aralkyl group with 1 or 2 carbon atoms in the alleyl part; or R ^ denotes an aryl group which is optionally substituted by a halogen atom or by a straight or branched chain alkyl or alkoxy group having 1 to 3 carbon atoms, or a cycloalkylalkyl group, the cycloalkyl part containing 3 to 7 carbon atoms and the alkyl part containing 1 or 2 carbon atoms ; R ^ "denotes a hydrogen atom or a straight or branched-chain alkyl group with not more than 4 carbon atoms, T and!, Which may be identical or different, each denote an oxygen or sulfur atom or a sulphinyl group and m is a number of 1 to 7], whose position in the benzene ring is either in the para position to the group -NHCSIHCOOR ¹ or in the para position to the group -JTHCOAZ, A is a divalent straight-chain aliphatic hydrocarbon radical with no more than 4 carbon atoms that is saturated or can be unsaturated and optionally by at least a methyl group can be substituted and 609831/1003 ... 91 - Z is a group of the general formula \ 7 R, JK or II III where R represents a hydrogen atom or a straight or branched chain alkyl group with not more than 4 carbon atoms, R a hydrogen atom or a straight or branched chain alkyl group with not more than 4 carbon atoms or a phenylalkyl group with 1 or 2 carbon atoms in the alkyl part and R ¹ a Denotes hydrogen atom or a straight or branched chain alkyl group with not more than 4 carbon atoms, or R and R together with the adjacent nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, one or two further heteroatoms selected from the ring Group oxygen, nitrogen and sulfur and which can optionally be substituted by one or more straight or branched chain alkyl groups each containing not more than 6 carbon atoms and wherein X® is a pharmaceutically or agriculturally acceptable anion. 2. Benzene derivatives according to claim 1, wherein R is a Group of the formula —SR ⁵ , -SOR ⁵ , -SO ₀ R ⁵ , -OR ⁵ , -SGONH ₀ or AA · Ζ έ <- -OJ (CH ₀ ) 0? R ^ denotes, where R ^ is a straight or branched chain g ₁₁₁ branched chain Alkyl group having not more means than 6 carbon atoms, a Oycloalkylgruppe having 3 to 7 carbon atoms, a straight or branched alkenyl or alkynyl group having 3 to 6 carbon atoms, an aralkyl group having 1 or 2 carbon atoms in the alkyl moiety or A _r yl group, and R, R , T, T and m are as defined in claim 1. 3. Benzene derivatives according to claim 1 or 2, wherein Z is a group of the formula II according to claim 1 and X is a phar- 609831/1003 means pharmaceutically acceptable anion. 2 5 4 9 A 1 7 4. Benzene derivatives according to claim 3, wherein X ^ a Chloride or methanesulfonate ion "means. 5. Benzene derivatives according to claim 1, wherein R is a methyl group, R ^{2 is} a group of the formula -SR ^, -SOR ^ or -OR ^ (where R ^ is a straight or branched chain alkyl group with 2 "to 4 carbon atoms, a cycloalkyl group with 3 "to 7 carbon atoms, a benzyl group or a phenyl group" is), A is a methylene, ethylene or ethylidene group and Z is a group of the formula II or III ", where R and R 'are each a hydrogen atom or a straight or branched-chain alkyl group with 1 "to 3 carbon atoms and in formula II (if present) R denotes a hydrogen atom and X® denotes a halide ion or a methanesulfonate ion. 6. benzene derivatives according to claim 1, wherein R is a 2 Methyl group, R a phenylthio or cycloperfcylthio group, A a methylene, ethylene or ethylidene group and Z a group of the formulas II or III, where R and R 'are each methyl groups and in formula II (if present) R is a hydrogen atom and X ^ means a chloride or methanesulfonate ion. 7. Benzene derivatives according to claim 1, wherein R 'is a methyl or Athy! Group, R is a phenylthio group and Z is a group of the formula II, where R, R and R' are each a what s first off atom or a methyl group and X. © denotes a halide ion or a methanesulfonate ion, or Z denotes a group of the formula III in which R and R 'represent an atom or a methyl group. 6 7 group of formula III, in which R and R 'are each a hydrogen of f- 8. Benzene derivatives according to claim 5 or 7, wherein X® is a chloride ion. 9. 4- (3-Methox7carbonyl-2-thioureido) -3- (2-dimethylaminoacetamido-1-diphenyl thioether. 609831/1003 " ⁹³ ~ 2 b 4 y A1 7 10. 3- (3-Methoxycarbonyl-2-thioureido) -4- ( 2-dimethylaminoacetamido} diphenyl thioether. 11, 4'-chloro-3- (3-methoxycarbonyl-2-thioureido ) -4- (2-dimethylaminoacetamido-diphenylthioether, 12 _# 3- (3-Methoxycart> onyl ~ 2-thioxir eido) -4 'methyl-4- (2-dimethylaminoacetamido) diphenyl »thioether. 13. 4- (3-I '! Etho; cycarbonyl- 2-thioureido) -3- (2- dimethylarainoacetamido} diphenyl ether. 14. 1- (3-Methoxycarbonyl-2-thioureido) -2- ( 2-dimethylaminoacetamido) -4-methylthiobenzOLU, 15. 4-Allylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido Jbenzbl, - 16. 4-ethylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido )benzene- 17. 4-Benzylthio-1- (3-methoxycarbonyl- 2- thioureido) -2- (2-dimethylaminoacetamido) benzene. 18. 4-n -Butyl thio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido )benzene. 19. 4-Cyclopentylthio-1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene. 20. 4- (2-ethylthio ethylthio) -1- (3-me% hoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benz oi, 609831/1003 . . · 2 b 4 9 4 Ί ^; 21,4- (S-methoscycarbonyl-2-thioureido) -3- (2-dimethylamino acetamido) diphenyl sulfoxide. 22nd 4- (3-methoxycarbony 1-2-thioureido) -3- (2-pyrrolidin-1-yl-acetamido ) diphenyl thioether. 23, 4— (3-Methoxy carbonyl — 2 — thioureido) —3— (3— dimethylaminopropionamido) diphenyl thioether. 24, 3- (2-diethylaminoacetamido) -4- (3-methoxy carbonyl-2-thioureido) diphenyl thioether, . .. 25. 4- (3-Metho: cycarbonyl-2-thioureido) -3- (2-dJLmethylaminoacetamido) diphenyl ether, 26, 3- (2-diethylaminoacetamido) —4— (3— methoxycarbonyl-2-thioureido) diphenyl ether, 27, 4- (3-methoxy carbonyl-2-thioureido) -3- (2 ~ dimethylaminopropionamido) diphenyl thioether, 28, 4- (2-aminoacetamido) -3- (3-methoxycarbonyl-2-thioureido) diphenyl thioether,. 29, 4- (2-aminoacetamido) -3- (3- ethoxycarbonyl-2 * -thioureido) diphenyl thioether, 30, 3- (3-ffetho: cycarbonyl-2-thioureido) -4- [2- (N-methylamino) acetamido] diphenyl-thio ether. 31 »3— (2-Aminoacetamido) —4— (3 — methoxycarbonyl— 2-thioureido) diphenyl thioether. € 09831/1003 - ⁹⁵ "2b4ü417 32, 4- (2-aminoacetamido) -3- (3-metho3: ycarbonyl ~ 2-thioureido) ~ 4 ~ ^l ~ methyl-diphenyl thioether. 33, 3— (2 — Aminoacetamido} -4— (3-methojiy carbonyl-2-thiotireido) diphenyl ether. 34,4- (2-aminoacetamido) -4'-chloro-3- (3-methoxycarbonyl-2-thioureido) diphenyl thioether. 35 "1- (3-MethoKycarbonyl-2-thioureido) -2- (2- (2- dimethylaminoacetamido) -4-thiocyanatobenzdL. 36. 3- (2-Dimethylaminoacetamido) -4 ~ [3- (2-methylpropoxycarbonyl) ~ 2-thioureido] diphenyl- thioether. 37, 4- (3-n-Butoxycarbonyl ~ 2-thioure'ido) -3- ( 2-dimethylaminoacetamido) diphenyl thioether. 38.4 ~ (3 — Methoscycarbonyl— 2-thioureido} —3— (2-morpholinoacetamido) diphenyl thioether. 39, 4- (3-methoxycarbonyl-2-thioureido) -3- { 2-di-n-propylaminoacetamido) diphenyl thioether. 40, 2- (3-lthO2q ^ carbonyl-2-thioureido) -l- (2-dimethylaminoacetamido) -4-methylsulf.onyle-'benzene. _# 4- [2- (lt.hylthio) & hoxy] -1- (3-methoxycarbonyl-2-thioureido) -2- (2-dimethylaminoacetamido) benzene. 42,4- (3-methoxycarbonyl-2-thioureido) -3- (2-trimethylammonioacetylamine Diphenyl thioether «·« iodide * 609831/1003 43. Salts of a benzene derivative according to one of the claims 9 "to 41 with a pharmaceutically acceptable or in the agriculturally acceptable anion. 44. A hydrohalide salt or the methanesulfonate alkali of a benzene derivative according to any one of claims 9 to 41. 45. Pharmaceutical compositions, characterized in that they contain at least one active ingredient Benzene derivative according to any one of claims 1 to 44 together with a pharmaceutically acceptable carrier, excipient Cover included. 46. Pharmaceutical compositions according to claim 53, characterized in that the benzene derivative is one of the compounds according to claims 9 to 41, or a pharmaceutical an acceptable salt thereof, or the benzene compound of claim 42. 47. Pharmaceutical compositions according to claim 53 or 54 in the form of tablets, pills, capsules, balls, Pastes, gel or potion. 48. Pharmaceutical compositions according to claim 53, characterized in that it contains one of the compounds according to the examples as active ingredient. 49. drug Royal animal feed, characterized in that it contains a $ fo an animal feed and from 0.001 wt., And 3 wt. Of at least one benzene compound of any of claims T to 44. 50, 'concentrates or supplements as an additive to animal feed, characterized in that these at least one benzene compound according to one of claims 1 to 44 together with an inert, physiologically harmless one £ 09831/1003 Carriers or diluents containing the amount of benzene compound from 0.02 wt. 56 to 90 wt. $ Of the composition amounts to. . . 51. Medicinal animal feed according to claim 57 or concentrates or supplements therefor according to claim 58, characterized in that they are used as the active ingredient contain a compound according to the preceding examples. 52. Fungicidal compositions, characterized in that they contain as active ingredient at least one benzene compound according to any one of claims 1 to 44, wherein any anion X ^ ^{5 present} in the benzene compound is an agriculturally acceptable anion, together with one or more diluents which is compatible with the benzene compound and suitable for use in agricultural fungicidal compositions. 53. Therapeutic compositions for use as fungicides against fungi which are pathogenic in animals, thereby characterized in that they contain at least one benzene compound according to claims 1 to 44 as the active ingredient with a pharmaceutically acceptable carrier, excipient or coating. 54 · Fungicidal compositions according to claim 60, characterized in that they are one of the compounds according to included in the examples. 55. Method for the destruction of fungi which have a pathogenic effect on plants, characterized in that a fungicidal composition according to claim 60 on a high yield end / area which is infected with the fungi is applied. * l cultivated 60983 1/100 3 ■ 56. The method according to claim 63, characterized in that the fungicidal composition is applied to the productive area in an amount of 0.25 to 3 lbs (113g-136Og) benzene compound per acre (4046.8 m). 57. Method for the protection of seeds or seeds against fungi, characterized in that the seeds or seeds with a fungicidal composition according to claim 60 is treated. 58. A method for protecting fruits against fungi after harvest, characterized in that the fruits with a fungicidal composition according to claim 60. 609831/100 3 59. Process for the preparation of a benzene derivative of the general formula I according to claim 1, characterized in that one
1) equimolar amounts of an isothiocyanate of the general formula SCiTCO ₂ R ¹ IV wherein R is as defined in claim 1 with an amine of general formula NHCQAZ ¹ 2 · 1 wherein R and A are as defined in claim 1 and Z is a group of the formula II according to claim 1, where R and R ^{1 are} as defined in claim 1, R is a hydrogen atom and X ^ is a halide ion ", or Z is a Group of the formula III according to claim 1 "means, converts, so that a 1 Compound of formula I according to claim 1, wherein R, R and A are as defined in claim 1 and Z is the group Z as defined above; or that one 2) an amine of the general formula CSNHCOOR ¹ R ^{2 1} "VIII 1 p wherein R and R ^ are as defined in claim 1 with a compound the general formula X ¹ COAZ ² . IX 609831/1003 where X is a chlorine, bromine or iodine atom, A as in An 2 1 Claim 1 is defined and Z is a group Z as defined above means with the exception that neither R nor R ' according to the formula II or III from claim 1 is a hydrogen atom can mean, implements, so that a connection of the • \ 2 Formula I results from claim 1, wherein R, R and A as in An 2 claim 1 are defined and Z means the group Z, like them is defined above; or that one 3) an amine of the above general formula VIII with a compound the general formula HOOCAZ ² X wherein A is as defined in claim 1 and Z is as defined above, in the presence of a condensation agent in a suitable solvent at a temperature between O ⁰ C and the reflux temperature of the reaction mixture, so that a process 12th Bond of the formula I according to claim 1, wherein R, R and A are as defined in claim 1 and Z is the group Z as previously defined ^ means; or that one 4) a compound of the general formula NHCSNHCOOR ¹ Xt NHCOAX ¹ 12 1 wherein R, R and A are as defined in claim 1 and X is as is defined above with a) a compound of the general formula EER ⁶ R ⁷ XII ft 7 wherein R and R 'are as defined in claim 1 reacted, so that a compound of the general formula I according to claim 1 1 2 yields, wherein R, R and A are as defined in claim 1 and Z is the group Z as defined above, or with b) a compound of the general formula ER ⁵ R ⁶ R ⁷ XIII wherein R and R 'are as defined in claim 1 and R is 609831/1003 straight or branched chain alkyl group with no more than 4 carbon atoms "means, converts, so that a compound 1 2 formation of the "formula 1 results from claim 1, wherein R, R and A are as defined in claim 1 and Z is a group of the formula II from claim 1, where R ^ is a straight or branched chain alkyl group with not more than 4 carbon atoms R and R ^ are as defined in claim 1 and the anion Jr ^ is a halide ion derived from the halogen atom represented by X in the compound of formula XI above; or that one 5) a compound of the general formula I from claim 1, 1 ?
wherein R, R and A are as defined in claim 1 and Z is a group of the formula III from claim 1 (where R and R 'are as defined in claim 1) with a compound of the general formula R ⁵ X ² XIV _t u msets “ j.
v before R is as defined in claim 1 and X is an atom or a group corresponding to the anion χ "as defined in claim 1 means, so that a compound of the formula I is derived 1 2
Claim 1 yields, wherein R, R and A are as defined in claim 1 and Z represents a group of the formula II from claim 1, 5 6 7
wherein R, R and R are as defined in claim 1 and the anion Jr ^ is derived from the atom or group represented by the symbol X in the compound of formula XIV above; or that one
6) a compound of the general formula CSNHCOOR ¹ NHCOANR ⁶ R ⁸ wherein A, R ¹ , R ² and R ^{6 are} as defined in claim 1 and R ^{8 is} a suitable protecting group, for example a benzyloxycarbonyl group ₃ is reacted with a reagent for removing this protective group R, so that a compound of the formula I from claim 1 009831/1003. gives wherein R '(in the definition of Z in claim 1) represents a hydrogen atom and the various other symbols are as defined in claim 1; or that 7) a compound of the formula I from claim 1, wherein Z is a group of the formula II from claim 1, wherein Br is hydrogen (R ¹ , R ² , R ⁶ , R ⁷ , A and X® are as in Claim 1 defined), treated with a base so that a compound 1 2 of the formula I according to claim 1, wherein R, R and A as are defined in claim 1 and Z is a group of the formula III according to claim 1. 609831/1003